CN112245592A - 与通过蛋白诱导的体内细胞重编程的细胞转化相关的方法、系统和组合物 - Google Patents

与通过蛋白诱导的体内细胞重编程的细胞转化相关的方法、系统和组合物 Download PDF

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CN112245592A
CN112245592A CN202011127974.8A CN202011127974A CN112245592A CN 112245592 A CN112245592 A CN 112245592A CN 202011127974 A CN202011127974 A CN 202011127974A CN 112245592 A CN112245592 A CN 112245592A
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transduction reagent
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王建军
李倩倩
麦可·乔普
姜丰
吴国俊
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Qurgen Inc
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Abstract

提供了用于治疗需要其的受试者的方法，该方法包括将包含蛋白转导试剂修饰的重编程蛋白的药物组合物给予受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质。根据各方面，所述方法提供了蛋白转导试剂修饰的重编程蛋白向癌细胞——例如肿瘤细胞——以及病变组织的病变细胞的递送，并且提供了病变细胞通过蛋白诱导的原位细胞重编程向正常细胞的体内转化，而没有将核酸给予所述受试者。

Description

与通过蛋白诱导的体内细胞重编程的细胞转化相关的方法、 系统和组合物
本申请为分案申请，其原申请的申请日为2014年10月27日，申请号为201480071293.0，名称为“与通过蛋白诱导的体内细胞重编程的细胞转化相关的方法、系统和组合物”。
基金信息
本发明是在由国立卫生研究院/国立癌症研究所授予的基金No.1 R01 CA172480-01A1的政府支持下完成的。政府对本发明享有某些权利。
技术领域
本发明总体上涉及在需要其的受试者中治疗病理学病症的方法、系统和组合物。在具体的方面，本发明涉及用于蛋白诱导的体内细胞转化的方法、系统和组合物，用于在需要其的受试者中治疗病理学病症。
背景技术
尽管近来医学进步，但存在对用于治疗疾病和损伤的方法和组合物的持续需求。
发明内容
根据本发明的方面，提供了治疗需要其的受试者的方法，其包括将包含蛋白转导试剂修饰的重编程蛋白的药物组合物给予所述受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质。
根据本发明的方面，提供了治疗需要其的受试者的方法，其包括将包含蛋白转导试剂修饰的重编程蛋白的药物组合物给予所述受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质，其中所述受试者患有选自如下的疾病：癌症；胰腺疾病或损伤；心脏病或心脏损伤，例如急性心肌梗塞、慢性心肌梗塞和心力衰竭；肝损伤或肝病，例如家族性高胆固醇血症(FH)、Crigler-Najjar综合征和遗传性的酪氨酸血症I；动脉粥样硬化；神经系统疾病或损伤，例如脊髓损伤、外伤性脑损伤、肌萎缩侧索硬化、脊髓性肌萎缩和帕金森氏病；关节炎；关节疾病或损伤；血液病；糖尿病；肥胖症；肌肉疾病或损伤；软骨疾病或损伤；乳腺疾病或损伤；和血管疾病或损伤。
根据本发明的方面，提供了治疗患有以受损的细胞和/或有缺陷的细胞为表征的病症的受试者的方法，其包括将包含蛋白转导试剂修饰的重编程蛋白的药物组合物给予所述受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质。
治疗患有癌症的受试者的方法，其包括：将包含蛋白转导试剂修饰的重编程蛋白的药物组合物给予所述受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质。
根据本发明的方面，提供了治疗患有癌症的受试者的方法，其包括给予包含蛋白转导试剂修饰的重编程蛋白——其选自蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog——的药物组合物。
根据本发明的方面，提供了治疗患有癌症的受试者的方法，其包括给予包含蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog的药物组合物。
根据本发明的方面，提供了治疗患有脑肿瘤或乳腺癌的受试者的方法，其包括给予包含蛋白转导试剂修饰的重编程蛋白——其选自蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog——的药物组合物。
根据本发明的方面，提供了治疗患有脑肿瘤或乳腺癌的受试者的方法，其包括给予包含蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog的药物组合物。
根据本发明的方面，提供了治疗患有以受损的细胞和/或有缺陷的细胞为表征的病症的受试者的方法，其包括：将包含蛋白转导试剂修饰的重编程蛋白的药物组合物给予所述受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质，其中所述病症为心脏病或心脏损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c和蛋白转导试剂修饰的Tbox5；其中所述病症为肝病或肝损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的Foxa1、蛋白转导试剂修饰的Foxa2和蛋白转导试剂修饰的Foxa3；其中所述病症为肝病或肝损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hnf1a和蛋白转导试剂修饰的Foxa3；其中所述病症为动脉粥样硬化并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的CEBPα、蛋白转导试剂修饰的CEBPβ和蛋白转导试剂修饰的PU.1；其中所述病症为神经退行性疾病或神经元组织损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的Foxg1；如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1；如下中的一种或多种：蛋白转导试剂修饰的Ascl、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1和蛋白转导试剂修饰的NeuroD1；蛋白转导试剂修饰的Ngn2；如下中的一种或两者：蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的NeuroD1；如下中的一种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9；如下中的一种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2；蛋白转导试剂修饰的Dlx2；蛋白转导试剂修饰的Dlx2和蛋白转导试剂修饰的Ascl1；如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2；或如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Nurr1；其中所述病症为血液疾病或障碍并且所述药物组合物包含：蛋白转导试剂修饰的Oct4；其中所述病症为糖尿病、胰腺疾病或胰腺组织损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的Pax4，或如下中的一种或多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的MafA；其中所述病症为肥胖症并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Prdm16和蛋白转导试剂修饰的C/EBPb；其中所述病症为肌肉疾病或肌肉损伤并且所述药物组合物包含蛋白转导试剂修饰的MyoD；其中所述病症为关节炎或关节疾病或关节损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6；其中所述病症为乳腺疾病或乳腺组织损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1l；其中所述病症为血管疾病或血管损伤并且所述药物组合物包含如下中的一种或多种：蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1和蛋白转导试剂修饰的Gata2，或如下中的一种或多种：蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2，或如下中的一种或两种：蛋白转导试剂修饰的Sox7和蛋白转导试剂修饰的Sox18。
根据本发明的方面，提供了包含一种或多种选自如下的蛋白转导试剂-重编程蛋白的药物组合物：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c、蛋白转导试剂修饰的Tbox、蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的Foxa1、蛋白转导试剂修饰的Foxa2和蛋白转导试剂修饰的Foxa3，蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的CEBPα、蛋白转导试剂修饰的CEBPβ、蛋白转导试剂修饰的PU.1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的Foxg1、蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的NeuroD1、蛋白转导试剂修饰的Ngn2、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1、蛋白转导试剂修饰的Dlx2、蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Oct4、蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1、蛋白转导试剂修饰的Pax4、蛋白转导试剂修饰的MafA、蛋白转导试剂修饰的Prdm16、蛋白转导试剂修饰的MyoD、蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6，蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3、蛋白转导试剂修饰的Brca-1l、蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1、蛋白转导试剂修饰的Gata2、蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2、蛋白转导试剂修饰的Sox7和蛋白转导试剂修饰的Sox18。
根据本发明的方面，提供了包含两种或更多种选自如下的蛋白转导试剂修饰的重编程蛋白的药物组合物：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c和蛋白转导试剂修饰的Tbox5；如下中的两种或更多种：蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的Foxa1、蛋白转导试剂修饰的Foxa2和蛋白转导试剂修饰的Foxa3；如下中的两种或更多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hnf1a和蛋白转导试剂修饰的Foxa3；蛋白转导试剂修饰的CEBPα、蛋白转导试剂修饰的CEBPβ和蛋白转导试剂修饰的PU.1；如下中的两种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的Foxg1；如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1；如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1和蛋白转导试剂修饰的NeuroD1；蛋白转导试剂修饰的Ngn2；蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的NeuroD1；如下中的两种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Asc11、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9；如下中的两种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Asc11、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2；蛋白转导试剂修饰的Dlx2；蛋白转导试剂修饰的Dlx2和蛋白转导试剂修饰的Asc11；如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2；如下的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Nurr1；蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的Pax4；如下中的两种或更多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的MafA；蛋白转导试剂修饰的Prdm16和蛋白转导试剂修饰的C/EBPβ；如下中的两种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6；如下中的两种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1l：如下中的两种或更多种：蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1和蛋白转导试剂修饰的Gata2；如下中的两种或更多种：蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2；或蛋白转导试剂修饰的Sox7和蛋白转导试剂修饰的Sox18。
本发明的方法使得能够将蛋白转导试剂修饰的重编程蛋白递送至癌细胞(如肿瘤细胞)以及病变组织的病变细胞。
根据本发明的方面的方法提供了病变细胞通过蛋白诱导的原位细胞重编程向正常细胞的体内转化。根据本发明的方面的方法提供了癌细胞通过蛋白诱导的原位细胞重编程向正常细胞的体内转化。
根据本发明的方面，提供了蛋白转导试剂修饰的重编程蛋白用于将癌细胞或病变细胞原位重编程为随后被诱导分化为所述癌细胞或病变细胞所处的组织中的正常细胞的干细胞或瞬时蛋白诱导的多能干细胞的用途。
根据本发明的方面，提供了治疗癌症的方法，其不通过杀死癌细胞，而是通过给予(例如全身给药或局部给药)一种或多种蛋白转导试剂修饰的重编程蛋白将癌细胞转化为非癌细胞来体内治疗癌症。
附图说明
图1A是携带9L-颅内肿瘤的大鼠的脑的代表性MRI图像，示出了在9L脑肿瘤中QQ-铁蛋白的增强的渗透性和保留效应，表明经静脉内(i.v.)注射的QQ-铁蛋白通过增强的渗透性和保留效应被递送至9L脑肿瘤中，引起在携带9L-脑肿瘤的大鼠中的脑肿瘤的增强的负MRI图像；
图1B是携带9L-颅内肿瘤的大鼠的脑的代表性MRI图像，示出了在9L脑肿瘤中未经QQ修饰的铁蛋白没有增强的渗透性和保留效应，表明经静脉内注射的铁蛋白未进入9L脑肿瘤中并且在携带9L-脑肿瘤的大鼠中未观察到脑肿瘤的增强的负MRI图像；
图2A为携带4T1乳腺肿瘤的小鼠在尾静脉注射QQ-铁蛋白之前的代表性MRI图像；
图2B为携带4T1乳腺肿瘤的小鼠在尾静脉注射QQ-铁蛋白后0.5h的代表性MRI图像；
图2C为携带4T1乳腺肿瘤的小鼠在尾静脉注射QQ-铁蛋白后2h的代表性MRI图像；
图2D为携带4T1乳腺肿瘤的小鼠在尾静脉注射QQ-铁蛋白后3.5h的代表性MRI图像；
图2E为携带4T1乳腺肿瘤的小鼠在尾静脉注射QQ-铁蛋白后8h的代表性MRI图像；
图2F为携带4T1乳腺肿瘤的小鼠在尾静脉注射QQ-铁蛋白后18h的代表性MRI图像；
图3A是示出了通过Ki67测定监测的U251细胞和U251-piPSC的增殖的图；
图3B是示出了患者来源的原发性人GBM(12-14)细胞(正方形)和GBM(12-14)-piPSC(圆形)对烷化剂替莫唑胺的剂量依赖性的化疗药物敏感性的图；
图3C是示出了9L-细胞(正方形)和9L-piPSC(圆形)对卡铂的剂量依赖性的化疗药物敏感性的图；
图4A是示出了U251细胞和U251-piPSC的几种上皮和间质的标志物(包括E-钙黏着蛋白(E-cad)、β-连环蛋白(β-cat)、波形蛋白(VMT))的Western印迹的图，表明在细胞重编程过程中的间质至上皮的转化(MET)。此外，9L-细胞细胞重编程为9L-piPSC也引起胶质细胞原纤维酸性蛋白(GFAP)——星形细胞的标志物——的增强的表达。
图4B是示出了通过U251细胞和U251-piPSC的细胞迁移的体外测定确认U251细胞在根据本发明的方面的细胞重编程后致瘤性降低的图，表明体外U251-piPSC的迁移显著减少(p＜0.01)；
图4C是示出了通过U251细胞和U251-piPSC的侵入的体外测定确认U251细胞在根据本发明的方面的细胞重编程后致瘤性降低的图，表明体外U251-piPSC的侵入显著减少(p＜0.01)；
图4D是示出了与亲代4T1细胞和67NR细胞的那些特性相比的4T1-piPSC和67NR-piPSC的增殖减少的图，表明4T1细胞和67NR细胞在体外细胞重编程为4T1-piPSC和67NR-piPSC后致瘤性显著降低；
图4E是示出了与亲代4T1细胞的那些特性相比的4T1-piPSC的乳腺球形成减少的图，表明4T1细胞在体外细胞重编程为4T1-piPSC后致瘤性显著降低；
图4F是示出了与亲代4T1细胞的那些特性相比的4T1-piPSC的迁移减少的图，表明4T1细胞在体外细胞重编程为4T1-piPSC后致瘤性显著降低；
图4G是示出了与亲代4T1细胞的那些特性相比的4T1-piPSC的侵入减少的图，表明4T1细胞在体外细胞重编程为4T1-piPSC后致瘤性显著降低；
图5A是示出了U251细胞的细胞形态的图像；
图5B是示出了间接与U251-piPSC共培养40-64小时的U251细胞的细胞形态的变化的图像，指示了间质至上皮的转化并证明了U251-piPSC对U251细胞的旁观者效应；
图5C是示出了以U251-piPSC和U251细胞1∶1的比率间接与U251-piPSC共培养的U251-piPSC和U251细胞的增殖显著减少的图，表明经共培养的U251细胞的致瘤性显著降低并且支持了旁观者效应的观察结果；
图5D是示出了以1∶1和8∶1(U251∶U251-piPSC)的比率间接与U251-piPSC共培养的U251-piPSC和U251细胞的迁移显著减少(P＜0.005)的图，表明经共培养的U251细胞的致瘤性显著降低并支持了旁观者效应的观察结果；
图5E是示出了以1∶1和8∶1(U251∶U251-piPSC)的比率间接与U251-piPSC共培养的U251-piPSC和U251细胞的侵入显著减少(P＜0.005)的图，表明经共培养的U251细胞的致瘤性显著降低并支持了旁观者效应的观察结果；
图5F是示出了与4T1-piPSC共培养40小时的4T1细胞的增殖显著减少的图，表明经共培养的4T1细胞的致瘤性显著降低并支持了旁观者效应的观察结果；
图5G是示出了与4T1-piPSC共培养40小时的4T1细胞的迁移显著减少的图，表明经共培养的4T1细胞的致瘤性显著降低并支持了旁观者效应的观察结果；
图5H是示出了与4T1-piPSC共培养40小时的4T1细胞的侵入显著减少的图，表明经共培养的4T1细胞的致瘤性显著降低并支持了旁观者效应的观察结果；
图6A是示出了颅内植入9L细胞或9L-piPSC(n＝10)的大鼠在第14天的肿瘤体积(mm3)以及示出了与9L-肿瘤的那些相比的颅内9L-piPSC肿瘤体积显著减少的图，表明9L细胞在体内细胞重编程为9L-piPSC后致瘤性显著降低；
图6B是示出了皮下植入9L细胞和9L-piPSC的大鼠在植入后第25天的肿瘤质量(g)(n＝6)以及示出了与9L-肿瘤的那些相比的皮下9L-piPSC肿瘤重量显著减少的图，表明9L细胞在体内细胞重编程为9L-piPSC后体内致瘤性显著降低；
图6C是示出了在4T1-和4T1-piPSC植入后25天内使用肿瘤体积所测量的4T1-和4T1-piPSC肿瘤生长曲线的图，表明4T1细胞在体内细胞重编程为4T1-piPSC后显著的体内肿瘤停滞；
图6D是在4T1-和4T1-piPSC植入后第25天使用肿瘤重量所测量的4T1-和4T1-piPSC肿瘤生长曲线的图，表明4T1细胞在体内细胞重编程为4T1-piPSC后显著的体内肿瘤停滞；
图6E是示出了植入4T1细胞或4T1-piPSC的小鼠在植入后第25天的肺转移的图，表明由4T1细胞体内细胞重编程为4T1-piPSC引起的主要体内转移抑制作用；将肺分成200个区，对转移的数目进行计数并在y轴报告；
图6F是在#4脂肪垫植入4T1细胞和4T1-piPSC的小鼠的Kaplan-Meier存活曲线，表明在该250天存活实验期间，4T1-piPSC的存活显著延长，表明恶性癌细胞细胞重编程为piPSC显著降低亲代癌细胞的致瘤性和转移特性；
图7A是示出了在用溶于PBS缓冲液的QQ-试剂(n＝10)、QQ-SON蛋白1μg/天(n＝5)、QQ-SON蛋白5μg/天(n＝5)和QQ-SON蛋白10μg/天(n＝10)治疗持续每日治疗18天的大鼠中通过肿瘤体积测量的剂量依赖性的9L肿瘤生长曲线的图，其中治疗开始于9L细胞植入后第5天并在第23天处死大鼠；
图7B是示出了在用溶于PBS缓冲液的QQ-试剂(n＝10)、QQ-SON蛋白1μg/天(n＝5)、QQ-SON蛋白5μg/天(n＝5)和QQ-SON蛋白10μg/天(n＝10)治疗持续每日治疗18天的大鼠中的9L肿瘤重量的图，其中治疗开始于9L细胞植入后第5天并在第23天处死大鼠；
图7C是用溶于PBS缓冲液的QQ-试剂(实线，n＝6；中值存活时间＝21天)或QQ-SON蛋白(虚线，10μg/天，n＝8；中值存活时间＝127天)治疗持续每日治疗30天的患有皮下9L肿瘤的大鼠的Kaplan-Meier存活曲线(130天)，终点是肿瘤体积达到12cm3的时候；
图7D是示出了在25天的时程内通过乳腺中的肿瘤体积所监测的多种QQ-SON蛋白剂量对4T1-肿瘤生长的影响的图；
图7E是示出了在第25天多种QQ-SON蛋白剂量对乳腺中的4T1-肿瘤重量的影响的图；
图7F是示出了通过MRI成像确定的用QQ-SON蛋白(n＝8)或作为对照的QQ-PBS(n＝8)治疗的携带4T1-肿瘤的小鼠的肿瘤体积在不同时间点的变化的图，表明未经原发性肿瘤切除的主要肿瘤停滞；
图7G是示出了用QQ-SON蛋白(n＝8)或作为对照的QQ-PBS(n＝8)治疗的携带4T1-肿瘤的小鼠在第35天的肿瘤重量的图，表明未经原发性肿瘤切除的主要肿瘤停滞；
图7H是在未经原发性4T1乳腺癌切除的60天存活实验期间，用QQ-PBS(对照，虚线)和QQ-SON蛋白(治疗，实线)治疗的携带4T1-乳腺癌的小鼠的Kaplan-Meier存活曲线，如图7H所示。治疗开始于4T1-细胞植入后第5天。处死到达终点——包括肿瘤大小负荷、吃力的呼吸、无法控制的疼痛等——的小鼠；
图7I是示出了未经原发性肿瘤切除、在肺中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠的百分比的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7J是示出了未经原发性肿瘤切除、在淋巴结中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠的百分比的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7K是示出了未经原发性肿瘤切除、在肝中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠的百分比的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7L是示出了未经原发性肿瘤切除、在脾中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠的百分比的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7M是示出了未经原发性肿瘤切除、在肺中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠中的每只小鼠的平均数目的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7N是示出了未经原发性肿瘤切除、在淋巴结中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠中的每只小鼠的平均数目的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7O是示出了未经原发性肿瘤切除、在肝中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠中的每只小鼠的平均数目的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图7P是示出了未经原发性肿瘤切除、在脾中具有转移病灶的经QQ-SON或QQ-PBS治疗的携带4T1肿瘤的小鼠中的每只小鼠的平均数目的图，如在指定天通过MRI所观察到的，表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的在携带4T1的小鼠中的主要转移抑制作用；
图8是携带4T1-乳腺癌的小鼠在第18天手术切除原发性4T1-乳腺癌后的Kaplan-Meier存活曲线(250天存活期)，QQ-SON蛋白治疗开始于第6天。
具体实施方式
本文使用的科技术语旨在具有本领域普通技术人员所通常理解的含义。发现这些术语在多篇标准参考文献的上下文中被定义和使用，所述参考文献示例性地包括J.Sambrook和D.W.Russell，Molecular Cloning：A Laboratory Manual，Cold SpringHarbor Laboratory Press；第三版，2001；F.M.Ausubel，Ed.，Short Protocols inMolecular Biology，Current Protocols；第五版，2002；B.Alberts等人，MolecularBiology of the Cell，第四版，Garland，2002；D.L.Nelson和M.M.Cox，LehningerPrinciples of Biochemistry，第四版，W.H.Freeman&Company，2004；Engelke，D.R.，RNAInterference(RNAi)：Nuts and Bolts of RNAi Technology，DNA Press LLC，Eagleville，PA，2003；Herdewijn，P.(Ed.)，Oligonucleotide Synthesis：Methods andApplications，Methods in Molecular Biology，Humana Press，2004；A.Nagy，M.Gertsenstein，K.Vintersten，R.Behringer，Manipulating the Mouse Embryo：ALaboratory Manual，第三版，Cold Spring Harbor Laboratory Press；2002-12-15，ISBN-10：0879695919；Kursad Turksen(Ed.)，Embryonic stem cells：methods and protocolsin Methods Mol Biol.2002；185，Humana Press；Current Protocols in Stem CellBiology，ISBN：9780470151808。
除非另外明确说明或上下文中另外清楚说明，单数术语“一(a)”、“一(an)”和“所述(the)”不意为限制性的，并包括复数个指示物。
根据本发明的方面的方法、系统和组合物提供了体内蛋白诱导的细胞重编程以治疗需要其的受试者。
根据本发明的方面的方法、系统和组合物提供用于通过引入一种或多种QQ修饰的重编程蛋白到体内病变细胞或损伤细胞中，而不引入编码所述一种或多种重编程蛋白的核酸，将所述病变细胞或损伤细胞转化成正常细胞。
根据本发明的方面的方法、系统和组合物提供用于通过引入一种或多种QQ修饰的重编程蛋白到体内癌细胞中，而不引入编码所述一种或多种重编程蛋白的核酸，将所述癌细胞转化成非癌细胞。
根据本发明的方面，提供了治疗需要其的受试者的方法，其包括将包含蛋白转导试剂修饰的重编程蛋白的药物组合物全身地和/或局部地给予所述受试者，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质。
根据本发明的方面，提供了包含蛋白转导试剂修饰的重编程蛋白的药物组合物。
“蛋白转导试剂修饰的重编程蛋白”为已用蛋白转导试剂——在本文中也称为“QQ试剂”——处理的重编程蛋白。术语“蛋白转导试剂”是指有效地使与蛋白转导试剂非共价结合的蛋白被递送到哺乳动物细胞中并且一旦存在于哺乳动物细胞中就与该蛋白解离以将该蛋白适当递送到其适当的亚细胞位置的组合物。所述蛋白转导试剂——在本文中也称为“QQ试剂”——包括至少一种阳离子试剂、至少一种脂质和任选的增强剂。本文使用的术语“QQ修饰的重编程蛋白”及其语法变体等同于本文使用的“蛋白转导试剂修饰的重编程蛋白”及其语法变体。类似地，称为“QQ”蛋白的一种或多种蛋白表示蛋白通过用蛋白转导试剂处理而被修饰并且为“蛋白转导试剂修饰的重编程蛋白”。例如，术语“QQ-SON”是指通过用本文所述的蛋白转导试剂处理而被修饰以产生蛋白转导试剂修饰的重编程Sox2蛋白、Oct4蛋白和Nanog蛋白的Sox2蛋白、Oct4蛋白和Nanog蛋白的混合物。
合适的阳离子试剂的一个实例是聚乙烯亚胺(PEI)，例如，但不限于，PEI Mw 1,200(PEI 1.2K)、PEI Mw 2000(PEI 2K)、PEI Mw 4000(PEI 4K)和PEI Mw 8000(PEI 8K)。脂质可以是本领域技术人员已知的具有与本文列出的那些脂质相同的一般特性的任何脂质。这样的脂质的实例包括，但不限于，DOTMA(N-1(-(2，3-二油酰氧基)丙基-N，N，N-三甲基氯化铵；DOGS(二十八基酰胺基-甘氨酰精胺)；DOTAP，1，2-二油酰基-3-三甲基铵-丙烷；DOPE，1，2-二油酰基-sn-甘油-3-磷酸乙醇胺；POPC，1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱；和DMPE 1，2-二肉豆蔻酰-sn-甘油-3-磷酸胆碱。
任选地，所述蛋白转导试剂包括作为阳离子试剂的聚乙烯亚胺，并且所述脂质为DOTAP或DOTMA和DOPE或DOGS；POPC和DMPE；或DOTAP或DOTMA、DOPE或DOGS、POPC和DMPE。任选地，所述蛋白转导试剂为表1所述的QQ1a、QQ2a、QQ3a、QQ4a、QQ5a、QQ6a、QQ7a、QQ8a、QQ9a。
任选的增强剂可以是显著增强阳离子蛋白质的细胞负载的任何增强剂。在细胞培养物中的这样的增强剂的实例包括，但不限于MG132、蛋白酶抑制剂、CaCl2、DMSO和生长因子。也可使用其他增强剂，包括但不限于细胞膜表面活性剂。所述试剂还可以包括不影响该试剂功能的稳定剂和其他惰性载体。如表1所示，可以改变使用的浓度和具体化合物。
本文使用的术语“重编程蛋白”是指DNA结合转录因子蛋白或其有效部分，其影响基因的转录并且诱导由第一分化细胞类型至第二、不同的分化细胞类型的改变。由第一分化细胞类型至第二、不同的分化细胞类型的改变通常历经一个中间的、更少分化的细胞类型(例如包括蛋白诱导的多能干细胞的瞬时干细胞)。已经从人类和其他物种中分离出重编程蛋白和编码它们的核酸。重编程蛋白包括，但不限于，Asc1、Ascl1、Brca-1l、Brn2、C/EBPα、CEBPβ、c-MYC、Dlx2、EKLF、Erg1、Er71、Fli1、Foxa1、Foxa2、Foxa3、FoxC1、FoxC2、FOXG1、FOXP3、Gata1、Gata2、Gata3、Gata4、Gata6、GFI1、Hand2、Hb9、Hey1、Hey2、HNF4A、Hnf1a、Klf4、Lhx3、LIN28A、Lmx1a、Lsl1、MafA、MEF2c、Mytl1、MYF5、MyoD、NAB2、Nanog、NeuroD1、NEUROG2、NEUROG3、Nurr1、Oct4、Pdx1、Pax4、PAX5、Pax6、Prdm16、PU.1、RORγ、Runx2、SLC7A10、Slug、Sox2、Sox5、Sox6、Sox7、Sox9、Sox18、Stat5a、T-bet和Tbox5。这样的重编程蛋白的氨基酸序列是已知的，如在本文示为SEQ ID NOs：1-63的序列所示例的，以及在本文示为SEQ ID NOs：65-127的编码它们的核酸。
待被QQ修饰的重编程蛋白通过例如分离、合成或重组表达编码所述重编程蛋白的核酸的方法来获得。这样的蛋白也可是市售可得的。
术语“核酸”是指具有如下任意形式的多于一个核苷酸的RNA或DNA分子：包括单链、双链、寡核苷酸或多核苷酸。术语“核苷酸序列”是指单链形式的核酸的寡核苷酸或多核苷酸中的排序。
待被QQ修饰的重编程蛋白的重组表达包括编码所述蛋白的核酸的表达，其中所述核酸被包含在表达构建体中。
宿主细胞可以用编码所需的重编程蛋白的表达构建体转染，以使所述重编程蛋白在细胞中表达。
术语“表达构建体”和“表达盒”在本文中用于指含有所需的待表达的重编程因子的核酸编码序列并含有一种或多种表达可操作地连接的编码序列所必需或期望的调控元件的双链重组DNA分子。
可操作地用于表达所需蛋白的表达构建体包括，例如，处于可操作连接的启动子、编码所需蛋白的DNA序列和转录终止位点。
本文使用的术语“调控元件”是指控制核酸序列表达的一些方面的核苷酸序列。示例性的调控元件说明性地包括增强子、内部核糖体进入位点(IRES)、内含子；复制起点、多腺苷酸化信号(多聚A)、启动子、转录终止序列和有助于核酸序列的复制、转录、转录后加工的上游调控区。本领域普通技术人员仅利用常规实验即能够选择上述和其他调控元件并将其使用在表达构建体中。可使用公知的方法通过重组或合成产生表达构建体。
本文使用的术语“可操作地连接”是指一个核酸与第二个核酸处于功能性关系中。
在具体的方面，包含在表达盒中的调控元件为启动子。
术语“启动子”在本领域中是公知的，是指一种或多种与待转录的核酸序列可操作地连接并结合RNA聚合酶且允许转录开始的DNA序列。启动子通常位于编码待表达的肽或蛋白的核酸的上游(5′)。
内含启动子可以是组成型启动子或可提供可诱导的表达。本领域技术人员熟悉各种公知的启动子，并且能够选择适用于在特定环境中(例如在具体指明的细胞类型中)表达肽或蛋白的启动子。
对于在酵母宿主细胞中的表达，合适的启动子包括，但不限于，ADH1启动子、PGK1启动子、ENO启动子、PYK1启动子等；或可调控的启动子，例如GAL1启动子、GAL 10启动子、ADH2启动子、PH05启动子、CUP1启动子、GAL7启动子、MET25启动子、MET3启动子、CYC1启动子、HIS 3启动子、ADH1启动子、PGK启动子、GAPDH启动子、ADC1启动子、TRP1启动子、URA3子、LEU2启动子、ENO启动子、TP1启动子和AOX1。
对于在原核宿主细胞中的表达，合适的启动子包括，但不限于，噬菌体T7 RNA聚合酶启动子；trp启动子；乳糖操纵子启动子；trc启动子；tac启动子；araBAD启动子；ssaG启动子；pagC启动子、σ70启动子、dps启动子、spv启动子、SPI-2启动子；actA启动子、rps M启动子；四环素启动子、SP6启动子、细菌噬菌体T3启动子、gpt启动子和细菌噬菌体λP启动子。
其他合适的细菌启动子和真核启动子是公知的，例如，如在Sambrook等人，Molecular Cloning，A Laboratory Manual，1989第二版；和第三版，2001；Kriegler，GeneTransfer and Expression：A Laboratory Manual(1990)；和Ausubel等人，CurrentProtocols in Molecular Biology，2014中所记载的。
对于在真核细胞中的表达，可包括在表达构建体中的启动子包括，但不限于，巨细胞病毒立即早期启动子；单纯疱疹病毒胸苷激酶启动子；早期和晚期SV40启动子；磷酸甘油酸激酶(PGK)启动子；存在于来自反转录病毒的长末端重复序列的启动子；和小鼠金属硫蛋白-I启动子、β-肌动蛋白启动子、ROSA26启动子、热休克蛋白70(Hsp70)启动子、编码延伸因子1α(EF1)的EF-1α基因启动子、真核起始因子4A(eIF-4A1)启动子、氯霉素乙酰转移酶(CAT)启动子和Rous Sarcoma病毒的长末端重复区(RSV启动子)。
除了启动子，可包括一种或多种增强子序列，例如，但不限于，巨细胞病毒(CMV)早期增强子元件和SV40增强子元件。
其他内含序列包括内含子序列，例如β球蛋白内含子或通用内含子、转录终止序列和mRNA多聚腺苷酸化(pA)序列，例如，但不限于SV40-pA、β-球蛋白-pA和SCF-pA。
表达构建体可包括在细菌细胞中扩增所必需的序列，例如选择标记物(例如卡那霉素抗性基因或氨苄西林抗性基因)和复制子。
内部核糖体进入位点(IRES)为任选的内含核酸序列，其允许翻译起始于mRNA中的内部位点。IRES是本领域公知的，例如如Pelletier，J.等人，Nature，334：320-325，1988；Vagner，S.等人，EMBO Rep.，2：893-898，2001；和Hellen，C.U.等人，Genes Dev.15：1593-1612，2001中所记载的。
术语“转录终止位点”是指可操作地通过RNA聚合酶终止转录的DNA序列。转录终止位点通常位于编码待表达的肽或蛋白的核酸的下游(3′)。
在表达构建体中任选地包括前导序列。
编码所需蛋白的核酸的密码子优化可用于改善在特定的表达系统中的表达，例如通过提高翻译效率。编码所需蛋白的经选择的核酸可经密码子优化以用于在任何指定的宿主细胞中表达，所述细胞为原核的或真核的，例如，但不限于，细菌、昆虫细胞、酵母、真菌、鸟卵和哺乳动物细胞。
经表达的蛋白任选地包括N末端元件，如前导序列和/或N-末端蛋氨酸。
除了编码所需重编程蛋白的一种或多种核酸，在表达载体中还可包括一种或多种编码额外蛋白的核酸序列。例如，任选地包括编码报道子——包括，但不限于，β-半乳糖苷酶、绿色荧光蛋白和抗生素抗性报道子——的核酸序列。在其他实例中，任选地包括his-标签、GST-标签或MBP-标签。
可将编码重编程蛋白的核酸克隆到用于转化至原核细胞或真核细胞并表达所编码的肽和/或蛋白的表达载体中。本文使用的“表达载体”被定义为当被引入合适的宿主细胞、表达系统中时，可被转录和翻译而产生所编码的多肽的多核苷酸。
表达载体是本领域已知的，例如，包括质粒、粘粒、病毒和噬菌体。表达载体可以是，例如，原核载体、昆虫载体或真核载体。
例如，包括处于可操作连接的启动子、编码所需蛋白的DNA序列和转录终止位点的表达构建体包括在质粒、粘粒、病毒或噬菌体表达载体中。
特定的载体是本领域已知的，并且本领域技术人员会知晓用于特定目的的适当载体。
根据本发明的各方面，任何合适的表达载体/宿主细胞系统可用于给予受试者的转录因子的表达。
使用重组表达载体的重编程蛋白的表达通过将表达载体引入到真核或原核宿主细胞表达系统(例如昆虫细胞、哺乳动物细胞、酵母细胞、真菌、鸟卵、细菌细胞或本领域中公认的任何其他单细胞生物体或多细胞生物体)中来实现。
含有重组表达载体的宿主细胞被维持在所需蛋白在其中产生的条件下。可以使用已知的细胞培养技术来培养或维持宿主细胞，例如，在Celis，Julio主编，1994，CellBiology Laboratory Handbook，Academic Press，N.Y中记载的。可以由本领域技术人员选择并优化这些细胞的各种培养条件，包括与特定的营养成分、氧、张力、二氧化碳和降低的血清水平相关的培养基配方。
可将细菌细胞用作宿主细胞以产生重编程蛋白。在细菌细胞中的重编程蛋白表达和所产生的蛋白的纯化可以使用已知方案进行，例如在Paulina Balbás，Argelia Lorence主编，2004，Recombinant Gene Expression：Reviews and Protocols，Humana Press，NewJersey；Peter E.Vaillancourt，2003，E.Coli Gene Expression Protocols，SpringerScience&Business Media中所记载的。
任选地，当使用产生内毒素的宿主细胞类型时，纯化经重组产生的重编程蛋白以除去内毒素。例如，在蛋白纯化阶段，可增加使用10个柱体积的0.2％Triton X114以从细菌表达的重组重编程蛋白中除去内毒素的额外的洗涤步骤。
或者，为了产生在人类细胞中不引发内毒素反应的重组重编程蛋白，可将经遗传修饰的细菌菌株ClearColiTMBL21(DE3)用作宿主细胞，以使不需要去除内毒素。
对于在宿主细胞中的表达，可以使用任何用于将重组核酸引入到宿主细胞中的公知方法，例如磷酸钙转染、聚凝胺、原生质体融合、电穿孔、声致穿孔、脂质体和显微注射法，其实例记载于Sambrook等人，Molecular Cloning：A Laboratory Manual，Cold SpringHarbor Laboratory Press，2001；和Ausubel，F.等人，(主编)，Current Protocols inMolecular Biology，2014中。
无细胞表达系统任选地用于表达重编程蛋白，如在Ausubel，F.等人，(主编)，Current Protocols in Molecular Biology，2014中所记载的。
可将在本文示为SEQ ID NOs：1-63并由SEQ ID NOs：65-127的核酸序列编码的人类重编程蛋白及其变体用于根据本文所述的方面的方法中。
本文使用的术语“变体”是指编码重编程蛋白的核酸序列的变异，或其中一种或多种核苷酸或氨基酸残基已通过核苷酸或氨基酸取代、添加或缺失被修饰且保留参照核酸序列或重编程蛋白功能的重编程蛋白的变异。相比于相应的核酸序列或重编程蛋白，本文所述的核酸序列或重编程蛋白的变体以保守的功能特性为表征。
可以使用标准分子生物学技术，例如化学合成、位点定向诱变和PCR介导的诱变来引入突变。
本领域技术人员会理解，可引入一种或多种氨基酸突变而不改变所需重编程蛋白的功能特性。例如，可以进行一种或多种氨基酸取代、添加或缺失而不改变所需重编程蛋白的功能特性。
本领域技术人员可容易地确定重编程蛋白变体的生物学活性，例如使用本文所述的任何功能测定法或本领域中已知的其他功能测定法。
相比于相应的重编程蛋白，本文所述的重编程蛋白的变体以保守的功能特性为表征并且与参照重编程蛋白的氨基酸序列具有75％、80％、85％、90％、95％、96％、97％、98％、99％或更大的同一性。
当将参照重编程蛋白与变体比较时，除了在氨基酸序列中相应位置处的氨基酸的同一性，还可以考虑氨基酸相似性。“氨基酸相似性”是指相比于在参照蛋白中的相应氨基酸位置，在推定的同源物中的氨基酸同一性和保守性氨基酸取代。
相比于相应的重编程蛋白，本文所述的重编程蛋白的变体以保守的功能特性为表征并且与参照重编程蛋白的氨基酸序列具有75％、80％、85％、90％、95％、96％、97％、98％、99％或更大的相似性。
可以在参照蛋白中进行保守性氨基酸取代以制备变体。
保守性氨基酸取代是本领域公认的一个氨基酸被另一个具有相似特性的氨基酸取代。例如，每个氨基酸可被描述为具有如下特征中的一种或多种：带正电的、带负电的、脂肪族的、芳香族的、极性的、疏水性的和亲水性的。保守性取代是一个具有具体指定结构或功能特征的氨基酸被另一种具有相同特征的氨基酸取代。酸性氨基酸包括天冬氨酸、谷氨酸；碱性氨基酸包括组氨酸、赖氨酸、精氨酸；脂肪族氨基酸包括异亮氨酸、亮氨酸和缬氨酸；芳香族氨基酸包括苯丙氨酸、甘氨酸、酪氨酸和色氨酸；极性氨基酸包括天冬氨酸、谷氨酸、组氨酸、赖氨酸、天冬酰胺、谷氨酰胺、精氨酸、丝氨酸、苏氨酸和酪氨酸；和疏水氨基酸包括丙氨酸、半胱氨酸、苯丙氨酸、甘氨酸、异亮氨酸、亮氨酸、蛋氨酸、脯氨酸、缬氨酸和色氨酸；和保守性取代包括在每组内氨基酸之间的取代。还可以根据相对大小来描述氨基酸，丙氨酸、半胱氨酸、天冬氨酸、甘氨酸、天冬酰胺、脯氨酸、苏氨酸、丝氨酸、缬氨酸通常都被认为是小氨基酸。
变体可包括合成的氨基酸类似物、氨基酸衍生物和/或非标准氨基酸，举例说明性地包括但不限于，α-氨基丁酸、瓜氨酸、刀豆氨酸、氰丙氨酸、二氨基丁酸、二氨基庚二酸、二羟基-苯丙氨酸、黎豆氨酸、高精氨酸、羟脯氨酸、正亮氨酸、正缬氨酸、3-磷酸丝氨酸、高丝氨酸、5-羟色氨酸、1-甲基组氨酸、3-甲基组氨酸和鸟氨酸。
同一性百分比通过比较氨基酸序列或核酸序列——包括参照氨基酸序列或核酸序列和推定的同源物氨基酸序列或核酸序列——来确定。为了确定两个氨基酸序列或两个核酸序列的同一性百分比，对所述序列进行比对用于最佳比较目的(例如，可在第一氨基酸序列或核酸序列中引入空位，以与第二氨基酸序列或核酸序列进行最佳比对)。然后比较相应的氨基酸位置或核苷酸位置上的氨基酸残基或核苷酸。当所述第一序列上的位置被与所述第二序列中对应位置的相同的氨基酸残基或核苷酸占据时，所述分子在此位置上是相同的。所述两个序列之间的同一性百分比是所述序列共有的相同位置的数量的函数(即，同一性百分比(％)＝相同重叠位置的数量/位置总数×100％)。所比较的两个序列通常具有相同的长度或几乎相同的长度。
确定两个序列之间的同一性百分比也可使用数学算法来完成。用于测定同一性百分比的算法示例性地包括S.Karlin和S.Altshul，PNAS，90：5873-5877，1993；T.Smith和M.Waterman，Adv.Appl.Math.2：482-489，1981，S.Needleman和C.Wunsch，J.Mol.Biol.，48：443-453，1970，W.Pearson和D.Lipman，PNAS，85：2444-2448，1988的算法，以及其他纳入计算机化实现形式(computerized implementations)的算法，例如但不限于，GAP、BESTFIT、FASTA TFASTA；以及，例如纳入在Wisconsin Genetics Software Package，GeneticsComputer Group，575 Science Drive，Madison，Wis.中并可从国立生物技术信息中心(National Center for Biotechnology Information)公开获得的BLAST。
用于比较两个序列的数学算法的非限制性实例是Karlin和Altschul，1990，PNAS87：2264-2268，在Karlin和Altschul，1993，PNAS.90：5873-5877中被改良。这样的算法被纳入Altschul等人，1990，J.Mol.Biol.215：403中的NBLAST和XBLAST程序。利用NBLAST核苷酸程序参数组(例如，得分＝100、字长＝12)进行BLAST核苷酸搜索，以获得与本发明的核酸分子同源的核苷酸序列。利用XBLAST程序参数组(例如，得分＝50，字长＝3)进行BLAST蛋白搜索，以获得与本发明的蛋白分子同源的氨基酸序列。为了获得用于比较目的的空位比对，按照Altschul等人，1997，Nucleic Acids Res.25：3389-3402中所述使用Gapped BLAST。或者，使用PSI BLAST进行迭代检索——其检测分子间的远缘关系。当利用BLAST、GappedBLAST和PSI Blast程序时，使用各个程序的(例如XBLAST和NBLAST的)默认参数。用于序列比较所使用的数学算法的另一个优选的非限制性实例是Myers和Miller，1988，CABIOS 4：11-17中的算法。此样的算法被纳入ALIGN程序(2.0版本)——其为GCG序列比对软件包的一部分。当利用所述ALIGN程序比较氨基酸序列时，其使用PAM120权重残基表、空位长度罚分为12且空位罚分为4。
在允许或不允许空位的情况下，使用与上述那些类似的技术来确定两个序列之间的同一性百分比。在计算同一性百分比时，通常仅计数精确的匹配。
本领域技术人员会认识到，可分别引入一种或多种核酸或氨基酸突变而不改变给定的核酸或蛋白的功能特性。
如前所述，在本文示为SEQ ID NOs：1-63的人类重编程蛋白由SEQ ID NOs：65-127的核酸序列编码。应理解，由于遗传密码的简并性，替代的核酸序列编码特定的重编程蛋白，并且这类替代核酸可被表达以产生所需重编程蛋白。
术语“互补”是指核苷酸之间的Watson-Crick碱基配对，并且具体是指核苷酸彼此氢键合——胸腺嘧啶或尿嘧啶残基与腺嘌呤残基通过两个氢键连接；并且胞嘧啶残基和鸟嘌呤残基通过三个氢键连接。通常，一个核酸包括被描述为与具体指定的第二核苷酸序列具有“互补性百分比”的核苷酸序列。例如，一个核苷酸序列可与具体指定的第二核苷酸序列具有80％、90％或100％的互补性，表明在序列的10个核苷酸中有8、9或10个核苷酸与所述具体指定的第二核苷酸序列互补。例如，核苷酸序列3′-TCGA-5′与核苷酸序列5′-AGCT-3′是100％互补的。此外，核苷酸序列3′-TCGA-5′与核苷酸序列5′-TTAGCTGG-3′的一个区域是100％互补的。
术语“杂交”是指互补核酸的配对和结合。如本领域众所公知的，两个核酸之间发生不同程度的杂交，这取决于例如核酸互补的程度、核酸的解链温度(Tm)和杂交条件的严格性的因素。术语“杂交条件的严格性”是指杂交介质的温度、离子强度和组成(针对具体的常用添加剂，例如甲酰胺和Denhardt溶液)的条件。对具体指定的核酸的特定杂交条件的确定是常规的且是本领域中公知的，例如，如在J.Sambrook和D.W.Russell，MolecularCloning：A Laboratory Manual，Cold Spring Harbor Laboratory Press；第三版，2001；和F.M.Ausubel主编，Short Protocols in Molecular Biology，Current Protocols；第五版，2002中所记载的。高严格杂交条件是仅允许基本上互补的核酸杂交的那些。通常，具有约85-100％互补性的核酸被认为是高度互补的，并在高严格条件下杂交。中等严格杂交条件的实例是这样的条件，在该条件下具有中度互补性(约50-84％互补性)的核酸，以及具有高度互补性的核酸发生杂交。相比之下，低严格杂交条件是其中具有低度互补性程度的核酸发生杂交的那些。
术语“特异性杂交”和“特异性地杂交”是指特定的核酸与靶核酸的杂交，而基本上不与样品中除了靶核酸以外的核酸杂交。
如本领域技术人员所公知的，杂交和洗涤条件的严格性取决于若干因素，包括探针和靶点的Tm，以及所述杂交和洗涤条件的离子强度。实现所需杂交严格性的杂交和条件记载于例如Sambrook等人，Molecular Cloning：A Laboratory Manual，Cold SpringHarbor Laboratory Press，2001；和Ausubel，F.等人，(主编)，Short Protocols inMolecular Biology，Wiley，2002中。
高严格杂交条件的实例是，在含有6X SSC、5X Denhardt溶液、30％甲酰胺和100μg/ml退行性的鲑鱼精子的溶液中，长度超过约100个核苷酸的核酸于37℃下过夜杂交，然后在0.1×SSC和0.1％SDS的溶液中在60℃下洗涤15分钟。SSC是0.15M NaCl/0.015M柠檬酸钠。Denhardt溶液是0.02％牛血清白蛋白/0.02％FICOLL/0.02％聚乙烯吡咯烷酮。
根据本发明的方面，通过QQ修饰的重编程蛋白是经分离的蛋白。术语“经分离的蛋白”表示蛋白已经从生物材料(例如可存在于蛋白在其中产生的系统中的细胞、细胞碎片和其他蛋白)中分离。术语“经分离的蛋白”可以，但不必然表示蛋白是经纯化的。包括在本发明的方法和组合物中的经纯化的蛋白含有所包括的蛋白的质量的至少约1-100重量％，例如约25重量％、50重量％、75重量％、85重量％、95重量％、99重量％或大于约99重量％。
术语“受试者”是指需要治疗响应于细胞重编程的有益效果的疾病或损伤的个体，并且通常包括哺乳动物和鸟类，例如，但不限于，人类、其他灵长类动物、猫、狗、绵羊、牛、山羊、马、猪、家禽、兔和啮齿类(如大鼠、小鼠和豚鼠)。根据本发明的方面，所述受试者是人。
病症以受损的细胞和/或有缺陷的细胞为表征。
术语“治疗”用于指治疗由受损的和/或有缺陷的细胞为表征的病症(例如，受试者的疾病或损伤)，其包括：在受试者中抑制或改善疾病或损伤，例如减缓疾病的进展和/或减少或改善疾病或损伤的征象或症状。
以血管生成为表征的病症根据本发明的方法的方面治疗，并且以QQ修饰的重编程蛋白通过血管生成性血管的增强的渗透性和保留效应(EPR效应)的有效递送为表征。
根据本发明的方面治疗的以受损的细胞和/或有缺陷的细胞为表征的病症为多种人类病症，包括但不限于：癌症；心血管疾病或损伤例如急性和慢性心肌梗塞，局部缺血，心脏损伤，冠状动脉病，先天性心脏病，心肌病例如酒精性心肌病、致心律失常性右室心肌病、高血压性心肌病、扩张型心肌病、肥厚性心肌病、炎症性心肌病、缺血性心肌病、继发于全身代谢性疾病的心肌病、营养不良性心肌病(myocardiodystrophy)、致密化不全心肌病、限制性心肌病和瓣膜性心肌病；血管疾病或血管损伤；贫血；缺血性和出血性中风；代谢性疾病或病症，例如I型糖尿病和II型糖尿病，和肥胖症；神经系统疾病和损伤例如脊髓损伤，外伤性脑损伤，Huntington氏病，精神分裂症，Alzheimer病，肌萎缩性侧索硬化，共济失调，自闭症，Lyme病，脑膜炎，偏头痛，运动神经元病，运动障碍例如帕金森氏病，神经病，疼痛，神经性疼痛，脊髓病症，外周和中枢神经疾病，自主神经系统疾病，疾病发作例如癫痫，睡眠障碍，痴呆例如Alzheimer病，肌营养不良症，Charcot-Marie-Tooth神经病1A型和脱髓鞘疾病例如急性播散性脑脊髓炎、肾上腺脑白质营养不良、肾上腺脊髓神经病、多发性硬化、视神经脊髓炎、视神经炎和横贯性脊髓炎；创伤；炎症性病症；肝疾病和损伤例如肝疾病例如家族性高胆固醇血症(FH)，Crigler-Najjar综合征，遗传性酪氨酸血症I，暴发性肝衰竭，病毒性肝炎，药物诱发的肝损伤，肝硬化，遗传性肝功能不全例如由于Wilson病、Gilbert综合征或a1-抗胰蛋白酶缺乏症，肝胆管癌，自身免疫性肝病例如自身免疫性慢性肝炎或原发性胆汁性肝硬化；自身免疫疾病；骨关节炎；类风湿性关节炎；软骨疾病或损伤例如由于关节疾病，骨关节炎，软骨损伤，外伤性破裂或脱离，软骨发育不全，肋软骨炎，椎间盘脱出症，复发性多软骨炎(polychonritis)，肿瘤，软骨瘤，软骨肉瘤和多形性腺瘤；Crohn病和遗传异常。
使用本文所述的方法和组合物治疗的特定的癌症以异常的细胞增殖为表征，包括但不限于，肿瘤前期过度增殖、原位癌、肿瘤和转移。术语“治疗”用于指在受试者中治疗癌症，包括：在受试者中抑制或改善癌症，例如减缓癌症的进展和/或减少或改善癌症的征象或症状。
包括本发明的抗癌组合物的组合物的治疗有效量是在被治疗的受试者中具有有益作用的量。在患有癌症(例如以异常的细胞增殖为表征的病症，包括但不限于，肿瘤前期过度增殖、原位癌、肿瘤、转移、肿瘤、良性生长物或其他响应于本发明的组合物的病症)的受试者中，治疗有效量的QQ修饰的蛋白有效改善一种或多种癌症的征象和/或症状。例如，治疗有效量的组合物对于可检测地降低以异常的细胞增殖为表征的癌细胞的增殖是有效的，所述异常的细胞增殖包括但不限于肿瘤前期过度增殖、原位癌、肿瘤、转移、肿瘤、良性生长物或其他响应于所给予的QQ修饰的蛋白的病症。
这样的癌症包括实体癌和非实体癌，例如膀胱癌；乳腺癌；结肠直肠癌；子宫颈癌；食道癌；头颈癌；肾癌；肺癌；神经系统癌症，例如胶质母细胞瘤、星形细胞瘤、室管膜瘤、神经母细胞瘤、视网膜母细胞瘤、脑膜瘤、颗粒细胞瘤和神经鞘瘤；卵巢癌；胰腺癌；前列腺癌；皮肤癌；胃癌；睾丸癌；喉癌；脐尿管癌；或阴道癌。
根据本发明的方面的药物组合物包括QQ修饰的重编程蛋白和可药用的载体。
本文使用的术语“可药用的载体”是指对预期接收者通常是无毒的，并且不会显著抑制QQ修饰的蛋白或其他包括在组合物中的活性剂的活性的载体或稀释剂。
本发明的组合物通常包括约0.1-99％的QQ修饰的重编程蛋白。
适合递送至受试者的药物组合物可以各种示例性地包括如下的形式来制备：生理上可接受的无菌水溶液或非水溶液、分散液、悬浮液或乳液，和用于复水成无菌可注射溶液或分散液的无菌粉末。
药物组合物任选地包含缓冲剂、溶剂或稀释剂。
合适的水性和非水性载体的实例包括水，乙醇，多元醇例如丙二醇、聚乙二醇和甘油；植物油例如橄榄油；和可注射的有机酯例如油酸乙酯；以及它们中的任意两种或更多种的合适的混合物。
这样的制剂通过包括肠胃外给药的合适的途径给药。任选地，给药包括全身给药或局部给药。
这些组合物还可含有佐剂，例如防腐剂、湿润剂、乳化剂和分散剂。微生物作用的预防可通过各种抗细菌剂和抗真菌剂(例如对羟苯甲酸类、三氯叔丁醇、苯酚、山梨酸等)来确保。一种或多种任选地包括等渗剂，例如，糖类和或盐类例如氯化钠。
在具体的方面，将QQ-修饰的蛋白通过局部施用给药。
在具体的方面，局部制剂可以是软膏剂、洗剂、霜剂或凝胶剂。局部剂型例如软膏剂、洗剂、霜剂或凝胶剂基质记载于Remington：The Science and Practice of Pharmacy，第二十一版，Lippincott Williams&Wilkins，2006，p.880-882和p.886-888；和Allen，L.V.等人，Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems，第八版，Lippincott Williams&Wilkins，2005，p.277-297中。
药物组合物的可药用的载体和制剂是本领域已知的，示例性地包括，但不限于，如在Remington：The Science and Practice of Pharmacy，第21版，Lippincott，Williams&Wilkins，Philadelphia，PA，2006；和Allen，L.V.等人，Ansel’s Pharmaceutical DosageForms and Drug Delivery Systems，第八版，Lippincott，Williams&Wilkins，Philadelphia，PA，2005中所记载的。
包括QQ修饰的蛋白的药物组合物适于通过多种全身途径和/或局部途径——包括但不限于：肠胃外、口腔、直肠、鼻、肺、硬膜外、眼、耳、动脉内、心脏内、脑室内、颅内、真皮内、静脉内、肌肉内、腹膜内、骨内、鞘内、瘤内、膀胱内、皮下、局部、经皮和经粘膜，例如通过舌下、颊、阴道和吸入给药途径——给予受试者。
药物组合物的给药
本发明的组合物可以急性给药或慢性给药。例如，如本文所述的组合物可以作为单一剂量或以多个剂量在相对有限的时间段(例如数秒-数年)内给药。在其他实施方案中，给药可包括在数天-数年的时期内给药多个剂量，例如用于慢性治疗癌症。
治疗有效量的QQ修饰的蛋白会根据给药途径和所给予的组合物的形式和所给予的特定组合物、在受试者中所治疗的病症的严重性和类型、受试者的物种、受试者的年龄和性别以及待治疗的受试者的总体身体特征而改变。根据本公开内容和本领域公知常识，本领域技术人员可基于医疗实践中典型的这些和其他考虑事项来确定治疗有效量，而无需过多实验。通常，认为治疗有效量会在约0.001ng/kg体重-100mg/kg体重的范围内，任选地在约0.01ng/kg-1mg/kg的范围内，并且还任选地在约0.1ng/kg-0.1mg/kg的范围内。此外，可根据治疗是否会是急性的或持续的来调整剂量。
尽管可给予更多个剂量，通常给予1-100个剂量的QQ修饰的蛋白以治疗需要其的受试者。为了延续1天、1周、2周、4周、1个月、2个月、3-6个月或更长的疗程，可以一天两次、每天、每周两次、每周、每隔一周、每月或以一些其他间隔给予QQ修饰的蛋白。任选地重复疗程，并且如果需要的话可延长为长期治疗。
根据本发明的方面的方法的QQ修饰的蛋白的给药包括按照给药方案给药，以产生所需的响应。合适的剂量给药方案(schedual)取决于几个因素，例如包括受试者的年龄、体重、性别、病史和健康状况，所用的组合物的类型和给药途径。本领域技术人员能够容易地确定用于特定受试者的给药剂量和给药方案。
本发明的实施方案的方法包括给予作为药物制剂的QQ修饰的蛋白，例如通过全身给药或局部给药。示例性的给药途径包括，但不限于，肠胃外、口腔、直肠、鼻、肺、硬膜外、眼、耳、动脉内、心脏内、脑室内、颅内、真皮内、静脉内、肌肉内、腹膜内、骨内、鞘内、瘤内、膀胱内、皮下、局部、经皮和经粘膜，例如通过舌下、颊、阴道和吸入给药途径。
QQ修饰的蛋白可经肠胃外给药，例如，通过注射，例如静脉内注射、肌内注射、腹膜内注射、皮下注射、经皮注射、鞘内注射、颅内注射、脑脊髓内注射，和/或连续输注，例如通过静脉连续输注设备或脑脊髓内连续输注设备。
根据各方面，蛋白转导试剂修饰的重编程蛋白为DNA结合转录因子。根据本文所述的方面，给予蛋白转导试剂修饰的重编程蛋白对于在疾病或损伤部位原位重编程一种或多种细胞类型以体内治疗疾病或损伤是有效的。根据本文所述的方面，给予蛋白转导试剂修饰的重编程蛋白对于在疾病或损伤部位原位重编程一种或多种细胞类型，产生随后在疾病或损伤部位体内原位分化成正常细胞的瞬时干细胞以治疗疾病或损伤是有效的。
根据本发明的方面的治疗癌症的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗癌症的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗癌症的方法包括给予：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。这样的方法通过在癌症位点重编程癌细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗脑肿瘤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的各方面的治疗脑肿瘤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗脑肿瘤的方法包括给予：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。这样的方法通过在脑肿瘤位点重编程脑肿瘤细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗脑肿瘤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的NeuroD。根据本发明的方面的治疗脑肿瘤的方法包括给予：蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的NeuroD。这样的方法通过在胰腺癌位点重编程脑肿瘤细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗乳腺癌的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗乳腺癌的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗乳腺癌的方法包括给予：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。这样的方法通过在乳腺癌位点重编程乳腺癌细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗乳腺癌的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Gata3、蛋白转导试剂修饰的Brca-1和蛋白转导试剂修饰的State5a。根据本发明的方面的治疗乳腺癌的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Gata3、蛋白转导试剂修饰的Brca-1和蛋白转导试剂修饰的State5a。根据本发明的方面的治疗乳腺癌的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Gata3、蛋白转导试剂修饰的Brca-1和蛋白转导试剂修饰的State5a。根据本发明的方面的治疗乳腺癌的方法包括给予如下中的四种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Gata3、蛋白转导试剂修饰的Brca-1和蛋白转导试剂修饰的State5a。根据本发明的方面的治疗乳腺癌的方法包括给予：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Gata3、蛋白转导试剂修饰的Brca-1和蛋白转导试剂修饰的State5a。这样的方法通过在乳腺癌位点重编程乳腺癌细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗胰腺癌的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗胰腺癌的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。根据本发明的方面的治疗胰腺癌的方法包括给予：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog。这样的方法通过在胰腺癌位点重编程胰腺癌细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗胰腺癌的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的PDX1、蛋白转导试剂修饰的PAX4、蛋白转导试剂修饰的MafA和蛋白转导试剂修饰的Ngn3。根据本发明的方面的治疗胰腺癌的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的PDX1、蛋白转导试剂修饰的PAX4、蛋白转导试剂修饰的MafA和蛋白转导试剂修饰的Ngn3。根据本发明的方面的治疗胰腺癌的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的PDX1、蛋白转导试剂修饰的PAX4、蛋白转导试剂修饰的MafA和蛋白转导试剂修饰的Ngn3。根据本发明的方面的治疗胰腺癌的方法包括给予：蛋白转导试剂修饰的PDX1、蛋白转导试剂修饰的PAX4、蛋白转导试剂修饰的MafA和蛋白转导试剂修饰的Ngn3。这样的方法通过在胰腺癌位点重编程胰腺癌细胞而在该位点产生新的正常细胞。
根据本发明的方面的治疗心脏病或心脏损伤(例如由于急性或慢性心肌梗塞造成的损伤)的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c和蛋白转导试剂修饰的Tbox5。根据本发明的方面的治疗心脏病或心脏损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c和蛋白转导试剂修饰的Tbox5。根据本发明的方面的治疗心脏病或心脏损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c和蛋白转导试剂修饰的Tbox5。根据本发明的方面的治疗心脏病或心脏损伤的方法包括给予：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hand2、蛋白转导试剂修饰的MEF2c和蛋白转导试剂修饰的Tbox5。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的心肌细胞、平滑肌细胞和内皮细胞。
根据本发明的方面的治疗肝病或肝损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hnf1a和蛋白转导试剂修饰的Foxa3。根据本发明的方面的治疗肝病或肝损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hnf1a和蛋白转导试剂修饰的Foxa3。根据本发明的方面的治疗肝病或肝损伤的方法包括给予：蛋白转导试剂修饰的Gata4、蛋白转导试剂修饰的Hnf1a和蛋白转导试剂修饰的Foxa3。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的肝细胞。这样的肝病或肝损伤的实例包括：家族性高胆固醇血症(FH)、Crigler-Najjar综合征和遗传性的酪氨酸血症I。
根据本发明的方面的治疗肝病或肝损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的Foxa1、蛋白转导试剂修饰的Foxa2和蛋白转导试剂修饰的Foxa3。根据本发明的方面的治疗肝病或肝损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的Foxa1、蛋白转导试剂修饰的Foxa2和蛋白转导试剂修饰的Foxa3。根据本发明的方面的治疗肝病或肝损伤的方法包括给予：蛋白转导试剂修饰的Hnf1a、蛋白转导试剂修饰的Foxa1、蛋白转导试剂修饰的Foxa2和蛋白转导试剂修饰的Foxa3。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的肝细胞。这样的肝病或肝损伤的实例包括：家族性高胆固醇血症(FH)、Crigler-Najjar综合征和遗传性的酪氨酸血症I。
根据本发明的方面的治疗动脉粥样硬化的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的CEBP/α/p和蛋白转导试剂修饰的PU.1。根据本发明的方面的治疗动脉粥样硬化的方法包括给予CEBP/α/β和蛋白转导试剂修饰的PU.1。这样的方法通过在动脉粥样硬化位点重编程成纤维细胞而在该位点产生新的泡沫细胞和巨噬细胞。
根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的Foxg1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的Foxg1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的Foxg1。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的神经元。
根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的四种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a、蛋白转导试剂修饰的Nurr1、蛋白转导试剂修饰的Brn2和蛋白转导试剂修饰的Mytl1。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的谷氨酸能神经元。
根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1和蛋白转导试剂修饰的NeuroD1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1和蛋白转导试剂修饰的NeuroD1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1和蛋白转导试剂修饰的NeuroD1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1和蛋白转导试剂修饰的NeuroD1。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的谷氨酸能神经元。
根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Ngn2。这样的方法通过在疾病或损伤位点重编程星形细胞而在该位点产生新的谷氨酸能神经元。
根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的NeuroD1。根据本发明的方面的治疗神经退行性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Sox2和蛋白转导试剂修饰的NeuroD1。这样的方法在疾病或损伤的位点产生新的神经干细胞。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的四种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3和蛋白转导试剂修饰的Hb9。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的运动神经元。这样的神经性疾病的实例包括肌萎缩侧索硬化症(ALS)。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的三种或多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的四种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的五种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascll、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的六种或更多种：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Ascl1、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lhx3、蛋白转导试剂修饰的Hb9、蛋白转导试剂修饰的Lsl1和蛋白转导试剂修饰的Ngn2。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的运动神经元。这样的神经性疾病的实例包括肌萎缩侧索硬化症(ALS)。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予蛋白转导试剂修饰的。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的GABA神经元。这样的神经性疾病的实例包括脊髓性肌萎缩(SMA)。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予蛋白转导试剂修饰的Dlx2。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的GABA神经元。这样的神经性疾病的实例包括肌萎缩侧索硬化症(ALS)、脊髓性肌萎缩(SMA)和帕金森氏病。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Dlx2和蛋白转导试剂修饰的Ascl1。这样的方法通过在疾病或损伤位点重编程星形细胞而在该位点产生新的GABA神经元。这样的神经性疾病的实例包括脊髓性肌萎缩(SMA)。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的四种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Brn2、蛋白转导试剂修饰的Mytl1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Foxa2。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的多巴胺神经元。这样的神经性疾病的实例包括帕金森氏病。
根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Nurr1。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Nurr1。根据本发明的方面的治疗神经性疾病或神经元组织损伤的方法包括给予：蛋白转导试剂修饰的Asc1、蛋白转导试剂修饰的Lmx1a和蛋白转导试剂修饰的Nurr1。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的神经元。这样的神经性疾病的实例包括帕金森氏病。
根据本发明的方面的治疗血液疾病或血液障碍的方法包括给予：蛋白转导试剂修饰的Oct4。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的造血细胞。
根据本发明的方面的治疗糖尿病、胰腺疾病或胰腺组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的Pax4。根据本发明的方面的治疗糖尿病、胰腺疾病或胰腺组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的Pax4。根据本发明的方面的治疗糖尿病、胰腺疾病或胰腺组织损伤的方法包括给予：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的Pax4。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的胰腺β细胞。
根据本发明的方面的治疗糖尿病、胰腺疾病或胰腺组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的MafA。根据本发明的方面的治疗糖尿病、胰腺疾病或胰腺组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的MafA。根据本发明的方面的治疗糖尿病、胰腺疾病或胰腺组织损伤的方法包括给予：蛋白转导试剂修饰的Ngn3、蛋白转导试剂修饰的Pdx1和蛋白转导试剂修饰的MafA。这样的方法通过在疾病或损伤位点重编程胰腺外分泌细胞而在该位点产生新的胰腺β细胞。
根据本发明的方面的治疗肥胖症的方法包括给予如下中的一种或两者：蛋白转导试剂修饰的Prdm16和蛋白转导试剂修饰的C/EBPb。根据本发明的方面的治疗肥胖症的方法包括给予蛋白转导试剂修饰的Prdm16和蛋白转导试剂修饰的C/EBPb。这样的方法通过在疾病或损伤位点重编程白色脂肪细胞而在该位点产生新的棕色脂肪细胞。
根据本发明的方面的治疗肌肉疾病或肌肉损伤的方法包括给予：蛋白转导试剂修饰的MyoD。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的肌肉细胞。
根据本发明的方面的治疗关节炎、骨关节炎、软骨退变和/或软骨损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6。根据本发明的方面的治疗关节炎、骨关节炎、软骨退变和/或软骨损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6。根据本发明的方面的治疗关节炎、骨关节炎、软骨退变和/或软骨损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6。根据本发明的方面的治疗关节炎、骨关节炎、软骨退变和/或软骨损伤的方法包括给予：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Runx2、蛋白转导试剂修饰的Sox5和蛋白转导试剂修饰的Sox6。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的软骨细胞。
根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予蛋白转导试剂修饰的Brca-1。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予蛋白转导试剂修饰的Sox9和蛋白转导试剂修饰的Slug。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予蛋白转导试剂修饰的Stat5a和蛋白转导试剂修饰的Gata3。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予如下中的四种或更多种：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1。根据本发明的方面的治疗乳腺疾病或乳腺组织损伤的方法包括给予：蛋白转导试剂修饰的Sox9、蛋白转导试剂修饰的Slug、蛋白转导试剂修饰的Stat5a、蛋白转导试剂修饰的Gata3和蛋白转导试剂修饰的Brca-1。这样的方法通过在疾病或损伤位点重编程成纤维细胞而在该位点产生新的乳腺导管细胞。
根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1和蛋白转导试剂修饰的Gata2。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1和蛋白转导试剂修饰的Gata2。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1和蛋白转导试剂修饰的Gata2。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予：蛋白转导试剂修饰的Erg1、蛋白转导试剂修饰的Er71、蛋白转导试剂修饰的Fli1和蛋白转导试剂修饰的Gata2。这样的方法通过在疾病或损伤位点重编程细胞而在该位点产生新的内皮细胞。
根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的一种或多种：蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的两种或更多种：蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的三种或更多种：蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予：蛋白转导试剂修饰的Hey1、蛋白转导试剂修饰的Hey2、蛋白转导试剂修饰的FoxC1和蛋白转导试剂修饰的FoxC2。这样的方法通过在疾病或损伤位点重编程细胞而在该位点产生新的动脉内皮细胞。
根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予如下中的一种或两者：蛋白转导试剂修饰的Sox7和蛋白转导试剂修饰的Sox18。根据本发明的方面的治疗血管疾病或血管损伤的方法包括给予蛋白转导试剂修饰的Sox7和蛋白转导试剂修饰的Sox18。这样的方法通过在疾病或损伤位点重编程细胞而在该位点产生新的静脉内皮细胞。
联合治疗
根据本发明的方面给予治疗剂的结合物。
在一些方面，将两种或更多种QQ修饰的蛋白给予受试者以在需要其的受试者中治疗病症。
在其他方面，将至少一种QQ修饰的蛋白和至少一种额外的治疗剂给予受试者以在需要其的受试者中治疗病症。
在其他方面，将至少一种QQ修饰的蛋白和至少两种额外的治疗剂给予受试者以在需要其的受试者中治疗病症。
在一些方面，将两种或更多种QQ修饰的蛋白给予受试者以在需要其的受试者中治疗癌症。在其他方面，将至少一种QQ修饰的蛋白和至少一种额外的治疗剂给予受试者以在需要其的受试者中治疗癌症。在其他方面，将至少一种QQ修饰的蛋白和至少两种额外的治疗剂给予受试者以在需要其的受试者中治疗癌症。
术语“额外的治疗剂”在本文中用于指示化合物、化合物的混合物、生物大分子(例如核酸、抗体、蛋白质或其部分例如肽)或从生物材料例如细菌、植物、真菌或动物(特别是哺乳类动物)细胞或组织制备的提取物，所述提取物是在受试者中局部或全身起作用的一种或多种生物学、生理学或者药理学活性物质。
本发明的方法和组合物的方面所包括的额外的治疗剂包括，但不限于，抗生素、抗病毒剂、抗肿瘤剂、镇痛剂、退热剂、抗抑郁剂、抗精神病药物、抗癌剂、抗组胺剂、抗骨质疏松剂、抗骨坏死剂、抗炎剂、抗焦虑药、化疗剂、利尿剂、生长因子、激素类、非甾族类抗炎剂、类固醇和血管活性剂。
利用一种或多种QQ修饰的蛋白质和一种或多种额外的治疗剂的联合疗法可显示协同效应，例如，比单独使用一种或多种QQ修饰的蛋白质或一种或多种额外的治疗剂作为单一疗法可观察到的更大的治疗效果。
根据各方面，联合疗法包括：(1)包括一种或多种QQ修饰的蛋白以及一种或多种额外的治疗剂的药物组合物；和(2)一种或多种QQ修饰的蛋白与一种或多种额外的治疗剂的共给药，其中所述一种或多种QQ修饰的蛋白和所述一种或多种额外的治疗剂未被配制在同一组合物中。当使用单独的制剂时，相对于一种或多种额外的治疗剂的给药，一种或多种QQ修饰的蛋白可同时、在间歇的时间、在错开的时间、之前、之后或其组合给药。
联合治疗可使得用于本发明的方法中的一种或多种QQ修饰的蛋白和一种或多种额外的治疗剂的有效剂量降低以及它们的治疗指数增加。
任选地，治疗患有癌症或处于患癌风险的受试者的方法还包括辅助的抗癌治疗。辅助的抗癌治疗可以是抗癌剂的给药。
抗癌剂记载于例如在Goodman等人，Goodman and Gilman′s ThePharmacological Basis of Therapeutics，第八版，Macmillan Publishing Co.，1990中。
抗癌剂示例性地包括异恶唑乙酸(acivicin)、阿柔比星(aclarubicin)、阿考达唑(acodazole)、阿克罗宁(acronine)、阿多来新(adozelesin)、阿地白介素(aldesleukin)、阿利维A酸(alitretinoin)、别嘌醇(allopurinol)、六甲蜜胺(altretamine)、安波霉素(ambomycin)、阿美蒽醌(ametantrone)、氨磷汀(amifostine)、氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、氨茴霉素(anthramycin)、白砒(arsenic trioxide)、门冬酰胺酶(asparaginase)、曲林菌素(asperlin)、阿扎胞苷(azacitidine)、阿扎替派(azetepa)、阿佐霉素(azotomycin)、巴马司他(batimastat)、苯佐替派(benzodepa)、比卡鲁胺(bicalutamide)、比生群(bisantrene)、双奈法德(bisnafide dimesylate)、比折来新(bizelesin)、博莱霉素(bleomycin)、布喹那(brequinar)、溴匹立明(bropirimine)、马利兰(busulfan)、放线菌素(cactinomycin)、卡普睾酮(calusterone)、卡培他滨(capecitabine)、卡醋胺(caracemide)、卡贝替姆(carbetimer)、卡铂(carboplatin)、卡莫司汀(carmustine)、卡柔比星(carubicin)、卡折来新(carzelesin)、西地芬戈(cedefingol)、塞来昔布(celecoxib)、苯丁酸氮齐(chlorambucil)、西罗霉素(cirolemycin)、顺铂(cisplatin)、克拉屈滨(cladribine)、克立那托(crisnatol mesylate)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、地西他滨(decitabine)、右奥马铂(dexormaplatin)、地扎胍宁(dezaguanine)、甲磺酸地扎胍宁(dezaguanine mesylate)、地吖醌(diaziquone)、多西他赛(docetaxel)、多柔比星(doxorubicin)、屈洛昔芬(droloxifene)、屈他雄酮(dromostanolone)、达佐霉素(duazomycin)、依达曲沙(edatrexate)、依氟鸟氨酸(eflomithine)、依沙芦星(elsamitrucin)、恩洛铂(enloplatin)、恩普氨酯(enpromate)、依匹哌啶(epipropidine)、表柔比星(epirubicin)、厄布洛唑(erbulozole)、依索比星(esorubicin)、雌氮芥(estramustine)、依他硝唑(etanidazole)、依托泊苷(etoposide)、氯苯乙嘧胺(etoprine)、法倔唑(fadrozole)、法扎拉滨(fazarabine)、芬维A胺(fenretinide)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟尿嘧啶(fluorouracil)、氟西他滨(flurocitabine)、磷喹酮(fosquidone)、福司曲星(fostriecin)、氟维司群(fulvestrant)、吉西他滨(gemcitabine)、羟基脲(hydroxyurea)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊莫福新(ilmofosine)、白细胞介素II(interleukin II；IL-2；包括重组白细胞介素II或rlL2)、干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素β-n3、干扰素β-Ia、干扰素γ-Ib、异丙铂(iproplatin)、伊立替康(irinotecan)、兰瑞肽(lanreotide)、来曲唑(letrozole)、亮丙瑞林(leuprolide)、利阿唑(liarozole)、洛美曲索(lometrexol)、洛莫司汀(lomustine)、洛索蒽酿(losoxantrone)、马索罗酚(masoprocol)、美登素(maytansine)、盐酸氮芥(mechlorethaminehydrochloride)、甲地孕酮(megestrol)、美仑孕酮乙酸盐(melengestrol acetate)、马法兰(melphalan)、美诺立尔(menogaril)、巯基嘌吟(mercaptopurine)、甲氨蝶呤(methotrexate)、氯苯氨啶(metoprine)、美妥替哌(meturedepa)、米丁度胺(mitindomide)、米托卡星(mitocarcin)、丝裂红素(mitocromin)、米托洁林(mitogillin)、米托马星(mitomalcin)、丝裂霉素(mitomycin)、米托司培(mitosper)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、霉酚酸(mycophenolic acid)、奈拉滨(nelarabine)、诺考达唑(nocodazole)、诺拉霉素(nogalamycin)、奥马铂(ormnaplatin)、奥昔舒仑(oxisuran)、紫杉醇(paclitaxel)、培门冬酶(pegaspargase)、培利霉素(peliomycin)、戊氮芥(pentamustine)、培洛霉素(peplomycin)、培磷酰胺(perfosfamide)、哌泊溴烷(pipobroman)、嗪消安(piposulfan)、盐酸吡罗蒽醌(piroxantrone hydrochloride)、普卡霉素(plicamycin)、普洛美坦(plomestane)、卟吩姆钠(porfimer)、泊非霉素(porfiromycin)、泼尼莫司汀(prednimustine)、甲基苄肼(procarbazine)、嘌呤霉素(puromycin)、吡唑呋喃菌素(pyrazofurin)、利波腺苷(riboprine)、罗谷亚胺(rogletimide)、沙芬戈(safingol)、司莫司汀(semustine)、辛曲秦(simtrazene)、磷乙酰天冬氨酸(sparfosate)、稀疏霉素(sparsomycin)、锗螺胺(spirogermanium)、螺莫司汀(spiromustine)、螺铂(spiroplatin)、链黑菌素(streptonigrin)、链脲佐菌素(streptozocin)、磺氯苯脲(sulofenur)、他利霉素(talisomycin)、他莫昔芬(tamoxifen)、替可加兰(tecogalan)、替加氟(tegafur)、替洛蒽醌(teloxantrone)、替莫泊芬(temoporfin)、替尼泊苷(teniposide)、替罗昔隆(teroxirone)、睾内醋(testolactone)、硫味嘌吟(thiamiprine)、硫鸟嘌吟(thioguanine)、塞替派(thiotepa)、噻唑羧胺核苷(tiazofurin)、替拉扎明(tirapazamine)、拓扑替康(topotecan)、托瑞米芬(toremifene)、曲托龙(trestolone)、曲西立滨(triciribine)、三甲曲沙(trimetrexate)、曲普瑞林(triptorelin)、妥布氯唑(tubulozole)、尿嘧啶齐末(uracil mustard)、乌瑞替派(uredepa)、伐普肽(vapreotide)、维替泊芬(verteporfin)、长春碱(vinblastine)、硫酸长春新碱(vincristine sulfate)、长春地辛(vindesine)、长春匹定(vinepidine)、长春甘醋(vinglycinate)、长春罗新(vinleurosine)、长春瑞滨(vinorelbine)、长春罗定(vinrosidine)、长春利定(vinzolidine)、伏氯唑(vorozole)、折尼铂(zeniplatin)、净司他丁(zinostatin)、唑来膦酸(zoledronate)和佐柔比星(zorubicin)。
辅助的抗癌治疗可以是受试者或受试者身体的患病区域的放射治疗。
在以下实施例中对本发明的组合物和方法的实施方案进行举例说明。提供这些实施例是为了举例说明的目的，并且不应被认为是对本发明的组合物和方法的范围的限制。
实施例
实施例1
重编程蛋白表达和制备
质粒构建
分别将编码Oct4、Sox2、Klf4和c-Myc、Nanog、GATA4、Hand2、Mef2c和Tbox5重编程蛋白的各DNA亚克隆到sHT-pET30a细菌表达载体中，其中短的his-标签：‘HHHHHHSS’(SEQID NO：64)替换了来自Novagen的pET30a表达载体中的长的his-标签。因子Xa(IEGR)切割位点位于短的his标签和编码基因之间。细菌表达载体的序列通过DNA测序确认。
蛋白表达和纯化
将重编程蛋白的DNA构建体分别转化到大肠杆菌菌株BL-21(DE3)或ClearColiTMBL21(DE3)细菌细胞中。ClearColiTM BL21(DE3)细菌细胞用于生产无内毒素的重组重编程蛋白。选择单个菌落用于细菌蛋白表达。在简单的优化后，根据不同的蛋白用0.5-1.2mM IPTG诱导蛋白表达并在18℃下继续培养12-16小时。在含有6M尿素的结合缓冲液中收集细胞并超声处理几次以提取蛋白。根据关于修饰的手册，使用组氨酸结合树脂柱(Novagen公司)纯化所述重组重编程蛋白。通常将蛋白提取上清液上柱两次，用5×柱体积的结合缓冲液洗涤。当使用常规的细菌菌株BL21(DE3)制备重组重编程蛋白时，在蛋白纯化阶段可增加使用10倍柱体积的0.2％Triton X-114的额外的洗涤步骤，以从细菌表达的重组重编程蛋白中除去内毒素。将加载有重组蛋白的柱再次用10×柱体积的含有15-50mM咪唑的洗涤缓冲液洗涤。将纯化的蛋白用含有500mM咪唑的洗脱缓冲液从柱中洗脱。将纯化的蛋白用水充分透析并冻干成蛋白粉末。
实施例2
QQ修饰：表达的重编程蛋白用蛋白转导试剂修饰以产生蛋白转导试剂修饰的重编程蛋白
可通过改变组合物使其包括表1所示的试剂来调整蛋白转导试剂(QQ试剂)，以获得对于特定重编程蛋白和细胞类型的最佳蛋白转导效率。
对于体内施用，使总体积为1ml：
Figure BDA0002731529550000421
储液的聚乙烯亚胺(PEI)浓度：
Figure BDA0002731529550000422
储液的脂质浓度：
Figure BDA0002731529550000423
用包含溶于1-6M尿素的重编程蛋白和指定的PEI、脂质的PBS缓冲液使总体积为1ml。
根据蛋白溶解度，首先将重编程蛋白以0.5-10mg/ml的浓度溶解在磷酸钠缓冲液(pH7.0，NaCl 50mM)中。发现蛋白溶解度影响阳离子化效率。为了完全溶解蛋白，将蛋白溶液在室温下过夜搅拌(有或没有3mM的DTT持续过夜，取决于所述重编程蛋白是否具有半胱氨酸残基)。也可将蛋白溶解在1-6M尿素中以提高蛋白溶解度。
使用如下的方法制备脂质DOTAP/DOPE(1∶1)乳液：将1mg的DOTAP/DOPE(0.5mg∶0.5mg＝1∶1)混合物溶解在氯仿中并在N2气体下干燥。然后将干燥的脂质膜溶解于pH 7.0的PBS缓冲液中，并将脂质溶液在购自Fisher Scientific(Sonic Dismembrator，Model100)的具有微探针的超声波仪上使用7-8的功率超声处理3×30s。将脂质溶液在37℃再孵育2小时，直至悬浮液变成半澄清的。将所制备的乳液储存在4℃下，其在一个月内是稳定的。
根据上述配方，将QQ试剂的其他成分(不包括脂质乳剂或任选的Ca或DMSO)在管中混合。然后将QQ试剂在搅拌的同时非常缓慢地滴加到蛋白溶液中，然后加入脂质乳液。一旦完成，将所得的蛋白溶液在使用前于室温下放置4小时。在此期间，必须温和搅拌以将QQ试剂与蛋白溶液混合，并且也使蛋白修饰反应完成。如果观察到沉淀，可将蛋白溶液以14,000rpm离心15分钟以除去沉淀物。如果出现沉淀物，将使用上清液进行BCA蛋白测定以检查溶液中剩余的蛋白量。为了确保蛋白转移到细胞内的效率，经修饰的蛋白的浓度必须足够高，为＞0.1mg/ml。
通常，对于体内给药，根据蛋白溶解度以0.5-1.5mg/ml的浓度制备QQ修饰的蛋白。
可对每个蛋白单独进行QQ修饰，或对待被一起给予受试者的蛋白混合物进行QQ修饰。
任选地，对每个蛋白单独进行QQ修饰，将QQ修饰的蛋白一起混合数小时，然后以1ml/管等分到小管中，并储存在-20℃下——在该温度下所述蛋白在数月内是稳定的。
如果大多数重编程蛋白沉淀，可将另外的QQ试剂用于蛋白修饰。QQ系列试剂涵盖广泛的阳离子化试剂以及不同的脂质和增强剂，因而任何沉淀问题都得到解决。可重复上述过程以制备更高浓度的蛋白转导试剂修饰的重编程蛋白。
将蛋白转导试剂修饰的重编程蛋白通过脱盐柱以将蛋白转导试剂修饰的重编程蛋白与剩余的未反应原料分开。将经纯化的蛋白通过过滤器(截留值为0.22μm，用于在体内给药前灭菌)。可将经纯化的蛋白级分在灭菌前或灭菌后浓缩，例如通过使用自旋柱浓缩；所述蛋白级分是稳定的并可在-20℃下储存几周到几个月。
为了蛋白转移的最佳效率以及最小细胞毒性，也可使用不同的QQ试剂。此外，为了蛋白转移入细胞的最佳效率，将不同的蛋白用不同的QQ试剂修饰。通常，为了更好的体内递送效率，使用QQ5a-QQ9a。然而，这可能会引起更高的体内毒性。当使用QQ5a-QQ9a时，强调使用更低浓度的更大的PEI和脂质。
为了良好的体内递送效率，使用具有更少体内毒性的QQ1a-QQ4a。可以使用具有更高脂质浓度的QQ1-QQ4。
实施例3
将重编程蛋白溶解在具有2M尿素的50mM pH 7.4的磷酸钠中。根据配方新鲜配置蛋白转导试剂(QQ试剂)。用于该实施例中的QQ试剂为聚乙烯亚胺(PEI)1200(1.2K，0.05-1.0mg/ml)和DOTAP/DOPE(25-100μg/ml)的混合物。通过将QQ试剂与一种或多种重编程蛋白(例如Oct4/Sox2/Nanog：1mg/ml)在室温下混合4小时或在冷室过夜混合来进行重编程蛋白的QQ修饰。
实施例4
QQ蛋白通过静脉内注射递送至大鼠中的脑肿瘤中
铁蛋白为可用作磁共振成像(MRI)的阴性对照试剂的普遍存在的含铁蛋白。
在该实施例中，将铁蛋白或用QQ试剂处理以制备QQ-铁蛋白的铁蛋白静脉内注射至通过植入大鼠神经胶质肉瘤细胞系9L细胞而产生的患有脑肿瘤的大鼠中。
新鲜制备大鼠神经胶质肉瘤细胞系9L的细胞并在植入前调整到1×106细胞/ml。根据标准方案制备颅内异种移植物。麻醉Fisher大鼠并将其置于立体定位框架中，并暴露头骨。在向右侧3mm和前囟点的1mm前打孔，并使用具有安装在立体定位器(Bonaduz，GR，Switzerland)中的26s号针头的10-μl Hamilton注射器注射9L细胞(5μl中5×104个细胞)。将注射器降低到3.5mm的深度，然后升高至3.0mm的深度。以0.5μl/10s的速率注射肿瘤细胞，并且用Horsley的骨蜡覆盖颅骨切开术。9L细胞植入12天后，经大鼠尾静脉注射QQ-修饰的铁蛋白或单独的铁蛋白，100μg/100μl/只大鼠。注射4小时后，麻醉大鼠并将大鼠脑部通过MRI成像。MRI后，处死所述动物。将所提取的脑在4％多聚甲醛中固定过夜，然后包埋在石蜡中用于进一步分析。从每个块切下6μm薄切片并用苏木精和伊红染色。脑肿瘤的大小通过显微镜测定。
图1A和1B示出了QQ-铁蛋白靶向递送至大鼠中的9L-脑肿瘤中的MRI证据，并且在用单独的铁蛋白注射的大鼠的9L-脑肿瘤中没有可检测的铁蛋白。图1A是经尾静脉用QQ-铁蛋白注射的患有9L-脑肿瘤的大鼠的代表性MRI图像。箭头指向9L-脑肿瘤，黑色指示递送至该肿瘤的铁蛋白。图1B：用未经QQ修饰的铁蛋白注射的患有9L-脑肿瘤的大鼠的代表性MRI图像。虽然处死大鼠并确认其具有大的9L-脑肿瘤，但是在这种情况下在脑肿瘤中没有观察到铁蛋白。
使用血管标志物的抗体CD31和铁蛋白的抗体来进行经QQ-铁蛋白注射的9L-脑肿瘤组织切片的双重免疫染色。用DAPI染色切片中的9L-癌细胞的细胞核。在脑肿瘤的血管中观察到CD31和铁蛋白的重叠免疫染色，表明QQ-铁蛋白通过与脑肿瘤相关的血管生成性血管的增强的通透性和保留效应(EPR效应)而从血管中渗出。在经QQ-铁蛋白治疗的动物中，在靠近或紧邻血管的肿瘤细胞的细胞液内观察到铁蛋白的免疫染色，表明QQ-铁蛋白渗透到肿瘤细胞中。相比之下，在用未经QQ-修饰的铁蛋白处理的9L-肿瘤切片中的铁蛋白免疫染色表明未经QQ修饰的铁蛋白没有渗透到肿瘤细胞中，虽然免疫染色表明该未经修饰的铁蛋白也渗出肿瘤相关的血管生成性血管。在细胞之间观察到这些未经修饰的铁蛋白纳米颗粒，并且可能由于在组织内的细胞之间的流体而没有积聚，使得通过MRI没有观察到肿瘤中有未经QQ修饰的铁蛋白。
这些数据提供了铁蛋白通过QQ-蛋白递送技术靶向递送至大鼠中的脑肿瘤中的MRI证据，其通过组织学分析和脑组织切片的免疫染色来确认。
实施例5
QQ蛋白通过静脉内注射递送至小鼠中的乳腺癌中。
在该实施例中，将铁蛋白或用QQ试剂处理以产生QQ-铁蛋白的铁蛋白静脉内注射到通过植入小鼠转移性乳腺癌细胞系4T1细胞而产生的患有转移性乳腺癌的小鼠中。在小鼠中的小鼠转移性乳腺癌细胞系4T1细胞的植入是自发转移性乳腺癌的小鼠模型。
将4T1细胞植入到2月龄雌性BALB/c小鼠的乳腺(#4脂肪垫)中(在50μl/只小鼠中20000个4T1细胞)。在4T1细胞植入18天后，4T1肿瘤在小鼠乳腺中已经生长到直径为～1.0-1.5cm的大小。经尾静脉注射QQ-修饰的铁蛋白(100μg/50μl/只小鼠)。麻醉小鼠并在注射经QQ-修饰的铁蛋白之前和注射后0.5小时、2小时、3.5小时、8小时和18小时进行MRI成像。
图2A-F为该时程的代表性MRI图像，示出了在携带乳腺癌的小鼠的原发性肿瘤中的QQ-递送的铁蛋白为在原发性肿瘤中变暗的区域。该原发性肿瘤暗度是时间依赖性的并且在8小时达到最大值，然后强度开始下降。
使用普鲁士蓝染色和铁蛋白免疫染色通过组织学分析确认MRI结果。在QQ-铁蛋白注射后18小时对携带4T1-乳腺癌的小鼠的原发性肿瘤组织切片的免疫组织化学染色和普鲁士蓝染色示出了原发性肿瘤内阳性的铁蛋白和普鲁士蓝染色。该组织学结果确认了对携带4T1-肿瘤的小鼠的原发性肿瘤内的QQ递送的铁蛋白的MRI观察结果。
实施例6
Oct4和Klf4蛋白至携带4T1乳腺癌的小鼠的原发性肿瘤中的4T1-乳腺癌细胞的细胞核的QQ-蛋白递送
将4T1细胞(2×104个细胞/50μl/只小鼠)植入到雌性BALB/c小鼠中。肿瘤细胞植入15天后，制备Alexa Fluor594标记的Klf4。然后制备QQ-修饰的未标记的Oct4(QQ-Oct4)和QQ-修饰的Alexa Fluor594标记的Klf4。瘤内注射50μg QQ-Oct4蛋白和QQ-AlexaFluor594标记的Klf4蛋白。在注射后5小时处死小鼠并制备用于免疫染色和荧光显微镜的肿瘤组织切片。在原发性4T1-乳腺癌组织切片中的Oct4的免疫染色证明Oct4在4T1-癌细胞中的核定位以及与DAPI的共定位。荧光显微成像也示出了Klf4在原发性4T1-乳腺癌组织切片中的核定位以及与DAPI的共定位。
实施例7
GATA4、OCT4和SOX2到急性心肌梗塞后大鼠的受损心脏的QQ蛋白递送
通过腹膜内注射对心肌梗塞后的大鼠给药QQ-修饰的和荧光标记的GATA4、Sox2和Oct4，并将经QQ-修饰的蛋白和荧光标记的蛋白递送至动物的受损心脏组织。
根据制造商指定的方法，将GATA4、Sox2和Oct4各自用Alexa Fluor488标记。将经标记的GATA4、Sox2和Oct4蛋白用小的自旋柱纯化。然后将Alexa Fluor488-GATA4、AlexaFluor488-Sox2和Alexa Fluor488-Oct4进行QQ修饰以生成QQ-修饰的Alexa Fluor488-GATA4、QQ-修饰的Alexa Fluor488-Sox2和QQ-修饰的Alexa Fluor488-Oct4。
麻醉Lewis大鼠并进行冠状动脉结扎手术以在Lewis大鼠中引起心肌梗塞。冠状动脉结扎手术24小时后，将QQ-修饰的Alexa Fluor488标记的GATA4、QQ-修饰的AlexaFluor488标记的Sox2和QQ-修饰的Alexa Fluor488标记的Oct4(200μg/100μl/鼠)腹膜内注射到Lewis大鼠中。荧光标记的蛋白注射后7小时，处死大鼠并制备用于梗塞面积的Trichrome染色或用于使用α-肌动蛋白抗体——其为指示成熟心肌细胞的心肌标志物——的免疫染色的心脏组织切片。
荧光显微分析示出了Alexa Fluor488-GATA4蛋白与α-肌动蛋白免疫荧光的共定位，表明在冠状动脉结扎后腹膜内注射QQ-荧光标记的GATA4导致GATA4蛋白递送至受损心脏组织的创伤区。类似地，对Alexa Fluor488-Sox2和α-肌动蛋白免疫荧光的荧光显微分析表明在冠状动脉结扎后腹膜内注射QQ-修饰的Alexa Fluor488标记的Sox2导致Sox2蛋白在受损心脏组织的边缘区域的定位。最终，Alexa Fluor488-Oct4的荧光图像示出了注射的QQ-修饰的Alexa Fluor488-Oct4在较远的正常心脏组织区的定位。这些结果表明，通过腹膜内注射给药的荧光标记的和QQ-修饰的GATA4、Sox2和Oct4到达创伤区的受损心脏组织。这些数据证明了QQ-蛋白递送将这些蛋白靶向递送至受损心脏组织中。
实施例8
使用QQ-修饰的Sox2、Oct4和Nanog(SON)蛋白如下所述将包括9L-细胞系、U251-细胞系、U87-细胞系和来自患者的原发性GBM细胞系的恶性神经胶质瘤细胞重编程为蛋白诱导的多能干细胞(piPSC)：在第0天，接种神经胶质瘤细胞24小时以使它们在50mm的培养皿中生长。在第2天，将QQ-SON蛋白以0.5-2.0μg/ml添加到培养基中并培养24小时。次日，将新鲜的QQ-SON蛋白添加到新的培养基中并培养24小时。根据用于细胞重编程的神经胶质瘤细胞，将这样的循环重复5-7次。在细胞重编程的最后，将培养基更换为维持培养基持续2天。在细胞重编程过程中，出现piPSC菌落。在第8天，将整个培养皿传代以扩增所产生的piPSC。使用多能性标志物(包括细胞核标志物Oct4、Nanog、Rex-1和表面标志物ALP、Tra1-60和Tra1-81)对包括9L-piPSC的单层细胞和菌落的整个培养皿传代的神经胶质瘤-piPSC的免疫染色显示几乎所有细胞对这些多能性标志物都是阳性的。相比之下，对9L-细胞的免疫染色示出了对这些标志物的阴性染色。这些数据表明使用QQ-SON蛋白将9L-细胞细胞重编程为9L-piPSC的高转化效率。
这通过使用Nanog和Oct4的9L-piPSC的全孔(96孔)免疫染色来确认。当计数与阴性克隆相比的阳性9L-piPSC克隆时，发现平均96±2％的转化效率，见表2。对9L细胞的对照免疫染色示出对于Nanog和Oct4这两个多能性标志物的阴性染色。使用由EVOS自动荧光显微镜提供的软件通过阳性染色的菌落和单层9L-piPSC对比用DAPI染色的总菌落和单层细胞来计算由9L细胞到9L-piPSC的转化效率。将重复的96孔的9L-piPSC的免疫染色用于计算平均转化效率和标准偏差。
Figure BDA0002731529550000481
使用QQ-SON蛋白细胞重编程9L细胞以产生9L-piPSC(0.5ug/ml，Sox2∶Oct4∶Nanog＝1∶1∶1，连续循环五次)。
使用类似的细胞重编程方案，由4T1小鼠乳腺癌细胞产生4T1-piPSC。使用相同的全孔计数法(96孔)，4T1细胞到4T1-piPSC的重编程转化效率为96±1.3％，参见表3。
Figure BDA0002731529550000482
实施例9
使用QQ-修饰的Sox2、Oct4和Nanog(SON)蛋白如下所述将人类胶质母细胞瘤细胞系U251的细胞重编程为U251-piPSC：在第0天，接种U251胶质母细胞瘤细胞24小时以使它们在50mm的培养皿中生长。在第2天，将QQ-SON蛋白以0.5-2.0μg/ml添加到培养基中并培养24小时。次日，将新鲜的QQ-SON蛋白添加到新的培养基中并培养24小时。将这样的循环重复5-7次。在细胞重编程的最后，将培养基更换为维持培养基持续2天。在细胞重编程过程中，出现U251-piPSC菌落。在第8天，将整个培养皿传代以扩增所产生的U251-piPSC。
通过测定Ki67-阳性细胞的数目来测定U251和U251-piPSC的增殖活性。图3A为示出该测定结果的图，表明神经胶质瘤细胞细胞重编程为piPSC显著降低了它们的增殖，误差线代表三次独立实验的标准误差。
实施例10
使用QQ-修饰的Sox2、Oct4和Nanog(SON)蛋白如下所述将患者来源的原发性人多形性成胶质母细胞瘤(GBM)细胞系GBM(12-14)的细胞重编程为GBM-piPSC：在第0天，接种GBM细胞24小时以使它们在50mm的培养皿中生长。在第2天，将QQ-SON蛋白以0.5-2.0μg/ml添加到培养基中并培养24小时。次日，将新鲜的QQ-SON蛋白添加到新的培养基中并培养24小时。将这样的循环重复5-7次。在细胞重编程的最后，将培养基更换为维持培养基持续2天。在细胞重编程过程中，出现GBM1-piPSC菌落。在第8天，将整个培养皿传代以扩增所产生的GBM1-piPSC。
测定了患者来源的原发性人GBM(12-14)细胞(正方形)和GBM(12-14)-piPSC(圆形)对烷化剂替莫唑胺的剂量依赖性的化疗药物敏感性，结果示于图3B中。实验重复3次，平均值±SD，p＜0.01。与亲代胶质母细胞瘤细胞相比，GBM-piPSC对替莫唑胺的药物敏感性显著增强。
实施例11
使用QQ-修饰的Sox2、Oct4和Nanog(SON)蛋白如下所述将大鼠胶质母细胞瘤细胞系9L的细胞重编程为9L-piPSC：在第0天，接种9L神经胶质瘤细胞24小时以使它们在50mm的培养皿中生长。在第2天，将QQ-SON蛋白以0.5-2.0μg/ml添加到培养基中并培养24小时。次日，将新鲜的QQ-SON蛋白添加到新的培养基中并培养24小时。将这样的循环重复5-7次。在细胞重编程的最后，将培养基更换为维持培养基持续2天。在细胞重编程过程中，出现9L-piPSC菌落。在第8天，将整个培养皿传代以扩增所产生的9L-piPSC。
通过MTT测定法测定了9L细胞(正方形)和9L-piPSC(圆形)对卡铂的剂量依赖性的化疗药物敏感性，结果示于图3C中。实验重复3次，平均值±SD，P＜0.01。与亲代9L细胞相比，9L-piPSC对卡铂的药物敏感性显著增强。
实施例12
使用QQ-修饰的Sox2、Oct4和Nanog(SON)蛋白如下所述将小鼠乳腺肿瘤细胞系4T1的细胞重编程为4T1-piPSC：在第0天，接种4T1细胞24小时以使它们在50mm的培养皿中生长。在第2天，将QQ-SON蛋白以0.5-2.0μg/ml添加到培养基中并培养24小时。次日，将新鲜的QQ-SON蛋白添加到新的培养基中并培养24小时。将这样的循环重复5-7次。在细胞重编程的最后，将培养基更换为维持培养基持续2天。在细胞重编程过程中，出现4T1-piPSC菌落。在第8天，将整个培养皿传代以扩增所产生的4T1-piPSC。
通过测定Ki67-阳性细胞的数量来测定4T1-细胞和4T1-piPSC的增殖活性并发现4T1乳腺肿瘤细胞细胞重编程为4T1-piPSC显著降低了它们的增殖。
与4T1细胞的乳腺球形成相比，4T1-piPSC的乳腺球形成减少。
通过MTT测定法测定了4T1-细胞和4T1-piPSC对多柔比星和紫衫醇的剂量依赖性的化疗药物敏感性。与亲代4T1细胞相比，4T1-piPSC对多柔比星和紫衫醇的药物敏感性显著增强。
实施例13
神经胶质瘤细胞衍生的piPSC到三个胚层的体外分化
使用悬滴法制备用于神经胶质瘤-piPSC的胚体(EB)。将神经胶质瘤-piPSC EB置于自发的分化培养基中10天，然后使用外胚层、中胚层和内胚层的标志物免疫染色，示出了对于外胚层的PAX6的阳性免疫染色、对于中胚层的结蛋白的阳性免疫染色和对于内胚层的α-甲胎蛋白(AFP)的阳性免疫染色。对照9L细胞的免疫染色对这些标志物是阴性的。对于4T1-piPSC也获得了类似的结果，表明4T1-piPSC也分化成三个胚层。
实施例14
神经胶质瘤细胞衍生的piPSC到神经细胞谱系的体外分化
将神经胶质瘤-piPSC EB置于特定的神经细胞谱系诱导分化培养基中14天，然后使用神经细胞谱系标志物免疫染色，示出了对于神经元的T uj I的阳性免疫染色、对于星形细胞的GFAP的阳性免疫染色和对于神经干细胞的巢蛋白的阳性免疫染色。这些神经-特异性分化细胞也显示了神经细胞形态。对照9L细胞的免疫染色对这些标志物是阴性的。
实施例15
细胞重编程导致间质至上皮的转化(MET)和体外致瘤性的降低。
对U251细胞和U251-piPSC的几个上皮和间质的标志物(包括E-钙黏着糖蛋白(E-cad)、β-连环蛋白(β-cat)、波形蛋白(VMT))的Western印迹分析结果(参见图4A)表明在细胞重编程过程中的MET，其通过细胞形态变化和qRT-PCR结果确认。在U251细胞细胞重编程为U251-piPSC后，GFAP蛋白水平也显著增强，表明在细胞重编程过程中，细胞重编程引起U251细胞体外致瘤性的显著降低。将肌动蛋白表达用作内部对照。使用抗GFAP抗体对U251细胞和U251-piPSC的免疫染色确认了如在Western印迹中所示的在U251-piPSC中的GFAP蛋白表达的上调。此外，表达GFAP的细胞显示神经细胞的形态。
在细胞重编程后U251细胞的致瘤性降低已经通过U251细胞和U251-piPSC的细胞迁移(图4B)和侵入(图4C)的体外测定而确认，表明U251-piPSC的迁移和侵入显著减少(p＜0.01)。
类似地，比较了使用上皮的标志物：E-钙黏着糖蛋白和间质的标志物纤连蛋白对41-piPSC和4T1细胞的免疫染色，并表明尽管4T1细胞显示阳性的E-钙黏着糖蛋白免疫染色，但是4TI-piPSC显示更强的E-钙黏着糖蛋白免疫染色。相比之下，4T1细胞显示更强的纤连蛋白免疫染色并且4T1-piPSC表现出几乎阴性的纤连蛋白免疫染色。该结果确认4T1细胞在细胞重编程为4T1-piPSC的过程中的MET。此外，相比于亲代4T1细胞的那些特性，4T1-piPSC也表现出减少的增殖(图4D)、减少的乳腺球形成(图4E)、减少的迁移(图4F)和减少的侵入(图4G)，表明4T1细胞在体外细胞重编程为4T1-piPSC后显著降低的致瘤性。
实施例16
神经胶质瘤细胞和神经胶质瘤-piPSC之间的共培养表明，神经胶质瘤-piPSC显示出改变他们周围的神经胶质瘤细胞的表型的旁观者效应和降低的体外致瘤性。
观察到间接与U251-piPSC共培养40-64小时的U251细胞的细胞形态变化，表明经共培养的神经胶质瘤细胞的间质至上皮的转化(MET)。图5A为示出了U251细胞的细胞形态的图像，图5B为示出了间接与U251-piPSC共培养40-64小时的U251细胞的细胞形态的变化的图像。
使用抗-泛-钙粘着蛋白抗体通过对U251细胞、U251-piPSC、第一次(1st)共培养的U251细胞和第二次(2nd)共培养的U251细胞的免疫染色确认了该MET，表明泛-钙粘着蛋白在U251细胞中的细胞液/细胞核定位以及U251-piPSC和1st/2nd共培养的U251细胞的细胞膜/细胞核定位，暗示了在U251-piPSC中以及在1st/2nd共培养的U251细胞中的细胞-细胞粘附的重大增强。这指示在细胞重编程过程中和1st/2nd共培养的U251细胞的MET。2nd共培养是将经1st共培养的细胞置于跨孔插件(transwell insert)中，并将新鲜的U251细胞置于基底外侧室中的间接共培养实验。使用经区别标记的抗-GFAP和抗-Tuj1抗体对U251细胞和间接共培养的U251细胞的双重免疫染色示出了具有神经形态的共培养的U251细胞中的显著的GFAP蛋白表达，而U251细胞(纺锤体形态)不表达GFAP。
U251细胞、U251-piPSC和间接共培养的U251细胞通过Ki-67免疫染色的增殖测定的结果表明U251-piPSC和经共培养的U251细胞的增殖显著减少(图5C)。U251细胞、U251-piPSC以及以1∶1和8∶1的比例(U251∶U251-piPSC)直接共培养的U251细胞的迁移测定的结果(图5D)和侵入测定的结果(图5E)表明在与U251-piPSC共培养之后U251细胞的迁移和侵入显著减少(p＜0.005)。
在类似的共培养实验后，观察到与4T1-piPSC共培养的4T1细胞的MET。共培养的4T1细胞和4T1-piPSC的免疫染色表明这两种细胞具有E-钙黏着糖蛋白的高蛋白表达和纤连蛋白的更低的蛋白表达，确认了经共培养的4T1细胞的MET。此外，经共培养的4T1细胞也显示显著减少的增殖(图5F)、迁移(图5G)和侵入(图5H)，表明在与4T1-piPSC共培养40小时后4T1细胞的致瘤性显著降低。
患者来源的原发性脑肿瘤细胞GBM(12-14)与U251-piPSC的共培养也导致经共培养的患者来源的原发性脑肿瘤细胞的间质至上皮的转化和降低的致瘤性——U251-piPSC的旁观者效应。
这些结果表明piPSC的旁观者效应改变周围癌细胞的表型以降低致瘤性和恶性肿瘤。该旁观者效应表明更小数目的piPSC可通过该旁观者效应改变大量周围肿瘤细胞的恶性表型，提供了细胞转化癌症疗法的细胞机制。
实施例17
由恶性癌细胞产生的piPSC的显著降低的致瘤性和体内转移/浸润抑制作用。
在第一组的动物中，将相同数量的9L细胞或9L-piPSC(5×104个细胞/5μL)颅内植入Fisher大鼠中。在第二组的动物中，将相同数量的9L细胞或9L-piPSC(1×106个细胞/100μL)皮下植入Fisher大鼠中。
在第14天测量颅内植入9L细胞或9L-piPSC的大鼠(n＝10)的肿瘤体积(mm3)，参见图6A。在4T1-细胞植入25天后测量皮下植入9L细胞或9L-piPSC的大鼠(n＝6)以克计的肿瘤重量，参见图6B。结果示出了与9L-肿瘤的那些相比的颅内9L-piPSC肿瘤的体积显著降低和皮下9L-piPSC肿瘤的重量显著降低，表明9L细胞在细胞重编程为9L-piPSC后的致瘤性显著降低。该结果也通过对来自经9L细胞和9L-piPSC植入的动物的肿瘤的苏木精和伊红(H&E)染色得到确认，表明9L-细胞浸润的主要抑制作用，因为9L-piPSC颅内肿瘤显示出清楚的完整边界，而9L-颅内肿瘤显示出破碎的边界，且9L-肿瘤细胞主要浸润到正常脑组织中。
实施例18
由恶性乳腺癌细胞产生的piPSC的显著降低的致瘤性和体内转移/浸润抑制作用。
将相同数量的4T1细胞和4TI-piPSC(2×104个细胞/50μL)植入到2-3月龄的雌性BALB/c小鼠(20克)的#4脂肪垫中。在细胞植入后第5-7天观察4T1乳腺肿瘤。每天监测小鼠的肿瘤体积和体重。在第25天，处死小鼠并称重肿瘤。对于存活实验，一旦动物达到肿瘤负荷就将它们处死。
在4T1-和4T1-piPSC植入后第25天，通过肿瘤体积(图6C)和肿瘤重量(图6D)测量4T1和4T1-piPSC肿瘤生长，表明4T1细胞在细胞重编程为4T1-piPSC后显著的肿瘤停滞。
在细胞植入后第25天分析植入有4T1细胞和4T1-piPSC的小鼠的肺转移。在细胞植入后第25天，虽然植入有4T1细胞的所有小鼠显示出很多转移病灶，但是在植入有4T1-piPSC的小鼠中没有观察到肺转移(图6E)，表明由4T1细胞细胞重编程为4T1-piPSC引起的重大的转移抑制作用。该结果通过对携带4T1的小鼠和携带4T1-piPSC的小鼠的肺组织切片的H&E染色确认，表明在植入有4T1-piPSC的小鼠中没有肺转移。
在#4脂肪垫中植入4T1细胞和4T1-piPSC的小鼠的Kaplan-Meier存活曲线(图6F)证明携带4T1-piPSC的小鼠在该250天存活实验过程中的显著延长的存活。这些结果证明，恶性癌细胞到piPSC的细胞预编程显著地降低亲代癌细胞的致瘤性和转移特性，因此显著地延长了植入有4T1-piPSC的小鼠的存活。
实施例19
根据不同分化组织环境，肿瘤细胞衍生的piPSC体内分化成不同的正常组织。
对9L-颅内植入的大鼠的脑组织切片的H&E染色显示出主要神经胶质瘤血管生成至正常脑组织中以及脑肿瘤内严重出血，而在9L-piPSC颅内植入的大鼠中观察到更少的血管生成和出血。此外，9L-piPSC颅内植入的大鼠在大脑中的肿瘤附近也显示出新分化的神经细胞团(neural rosettes)。此外，对皮下植入9L-piPSC的大鼠的肿瘤组织载玻片的H&E染色示出了在肿瘤内的具有立方的且矮柱状的上皮细胞的未成熟汗腺和具有褐色黑色素的黑素细胞。对皮下植入9L-piPSC的大鼠的肿瘤组织载玻片的H&E染色也示出了具有两层上皮的皮肤上皮细胞以及具有更长形状和位于细胞基底部的细胞核的早期简单的柱状上皮细胞。
类似地，对携带4TI-piPSC的小鼠的肿瘤团块的H&E染色显示植入的4T1-piPSC体内分化成包括脂肪细胞(包括褐色和白色脂肪细胞)的正常乳腺组织以及成熟和未成熟的乳腺导管。
这些结果表明，根据不同分化组织环境，肿瘤细胞衍生的piPSC体内分化成不同的正常组织细胞。
实施例20
谱系追踪显示肿瘤细胞衍生的piPSC分化成正常组织。
为了确保肿瘤细胞衍生的piPSC分化成正常组织，制备表达GFP的9L-细胞和4T1-细胞。
制备GFP-9L-piPSC和GFP-4T1-piPSC。
用两种细胞类型进行谱系追踪实验。对于GFP-9L-piPSC，将细胞皮下植入到Fisher大鼠的左侧面。对于GFP-4T1-piPSC，将细胞植入到雌性BALB/c小鼠的#4脂肪垫。对于GFP-9L-piPSC植入的大鼠，在第10-15天观察到小肿瘤团块；对于GFP-4T1-piPSC植入的小鼠，在第20-25天观察到小肿瘤团块。在细胞植入后，将动物在不同天数时处死并收集肿瘤团块，用于制备用于H&E染色和免疫染色的组织切片。使用差异化的可检测标记物进行使用Tuj I和Nestin神经标志物抗体，脂连蛋白(脂肪细胞标志物)，角蛋白8、14、18(CK8，14，18)或角蛋白5、8(CK5，8)(乳腺导管标志物)的免疫染色。
对携带4T1-piPSC的小鼠的肿瘤团块的中心和边缘的H&E染色均显示在肿瘤团块中出现潜在的脂肪细胞和未成熟乳腺导管。
对从使用抗-Tuj I抗体的谱系追踪实验获得的GFP-9L-piPSC肿瘤团块的组织切片的免疫染色显示阳性的Tuj I免疫染色，其与相同组织切片的表达GFP的细胞的GFP荧光重叠。在组织切片中仅观察到重叠的Tuj I和GFP荧光图像，表明这些Tuj I阳性细胞源自表达GFP的9L-piPSC。Tuj I/GFP-阳性细胞显示出神经元细胞形态。该数据证明了表达GFP的9L-piPSC体内分化成Tuj I阳性神经元谱系细胞。
对从使用抗-巢蛋白抗体的谱系追踪实验获得的GFP-9L-piPSC肿瘤团块的组织切片的免疫染色显示出阳性的巢蛋白免疫染色，其与相同组织切片的表达GFP的细胞的GFP荧光重叠。在组织切片中仅观察到重叠的巢蛋白和GFP荧光图像，表明这些巢蛋白阳性细胞源自表达GFP的9L-piPSC。该数据证明了表达GFP的9L-piPSC体内分化成巢蛋白阳性神经元谱系细胞。
使用抗-脂联素抗体对携带4T1-piPSC的小鼠的肿瘤组织切片的免疫染色显示脂联素阳性免疫染色，其与来自表达GFP的细胞的绿色荧光重叠。在具有脂肪细胞形态的细胞的组织切片中仅观察到重叠的脂联素和GFP荧光，表明在携带4T1-piPSC的小鼠的肿瘤团块的中间存在脂肪细胞并且这些脂肪细胞源自植入的GFP-4T1-piPSC的分化，因为这些脂肪细胞表达GFP。
使用抗-CK8，18，14和抗-CK5，8抗体对携带4T1-piPSC的小鼠的肿瘤组织切片的免疫染色显示CK8，18，14-阳性免疫染色和抗CK5，8-阳性免疫染色，其与来自表达GFP的细胞的绿色荧光重叠。在具有乳腺导管形态的细胞的组织切片中仅观察到重叠的CK8，18，14-阳性荧光或抗-CK5，8-阳性荧光和GFP荧光，表明源自植入的GFP-4T1-piPSC的分化的未成熟的乳腺导管的存在，因为这些乳腺导管表达GFP。
实施例21
QQ-SON蛋白-诱导的肿瘤的体内细胞重编程治疗
为了产生携带9L-肿瘤的大鼠，将9L细胞(1×106个细胞/100μL)皮下植入到Fisher大鼠中。9L-植入后5天，每天以1μg/天(n＝5)、5μg/天(n＝5)或10μg/天(n＝10)通过肿瘤内注射给予QQ-SON蛋白，持续每日治疗18天。通过肿瘤内注射给予溶于PBS缓冲液的QQ-试剂以控制大鼠(n＝10)。每天监测大鼠的肿瘤体积和体重。在第23天，处死大鼠并称重肿瘤。
通过体积测量肿瘤生长(参见图7A)和以克计的肿瘤重量(参见图7B)。在23天处死大鼠并称重肿瘤。该数据表明QQ-SON治疗诱导原位细胞重编程——其导致肿瘤停滞。
为了确定QQ-SON蛋白治疗对于皮下植入9L细胞的大鼠的存活的影响，在9L细胞植入后第5天，用溶于PBS的QQ-试剂(n＝8；中值存活时间＝21天)或用QQ-SON蛋白(10μg/天，n＝8；中值存活时间＝127天)治疗大鼠，持续每日治疗30天。一旦动物达到肿瘤负荷(＜12em3)就处死它们。Kaplan-Meier存活曲线(130天)示于图7C中。该数据表明QQ-SON蛋白治疗显著延长携带9L肿瘤的大鼠的存活。
实施例22
QQ-SON蛋白诱导的肿瘤的体内细胞重编程治疗
为了产生携带原位4T1乳腺癌的小鼠，将4T1细胞(2×104个细胞/50μL)植入到2-3月龄雌性BALB/c小鼠(20克)的#4脂肪垫中。在细胞植入后5-7天观察到4T1乳腺肿瘤。每天监测小鼠的肿瘤体积和体重。在第25天，处死小鼠并称重肿瘤。对于存活实验，一旦动物达到包括肿瘤负荷(＜2g)、导致呼吸吃力的转移、无法控制的疼痛等的终点就将它们处死。
给予不同剂量的QQ-SON蛋白(0.5μg QQ-修饰的SON蛋白/只小鼠、1.25μg QQ-修饰的SON蛋白/只小鼠或2.5μg QQ-修饰的SON蛋白/只小鼠)，并与QQ-PBS对照比较。通过在25天的时程内测量肿瘤体积(图7D)以及在第25天测量以克计的肿瘤重量(图7E)来测定功效。
在进一步的实验中，通过MRI测定在35天的时程期间用QQ-SON蛋白(n＝8)或作为对照的QQ-PBS(n＝8)治疗的小鼠的肿瘤体积(参见图7F)，并通过在第35天称重来测定两组的肿瘤重量(参见图7G)。QQ-SON蛋白治疗导致未经原发性肿瘤切除的主要肿瘤停滞。
分析小鼠以测定如在指定天数时通过MRI所观察到的在经QQ-SON和QQ-PBS治疗的未经原发性肿瘤切除的携带4T1的小鼠的肺(图7I和7M)、淋巴结(图7J和7N)、肝(图7K和7O)和脾(图7L和7P)中的转移病灶的数量和百分比。这些结果表明，与经QQ-PBS治疗的小鼠相比，经QQ-SON治疗的小鼠在4T1-细胞植入后更晚的时期显示出转移，在肺、淋巴结中显示更少的转移病灶并且在肝和脾中没有观察到转移病灶。该数据表明由未经原发性肿瘤切除的QQ-SON蛋白治疗导致的携带4T1的小鼠中的主要转移抑制作用。
实施例23
对用QQ-PBS和QQ-SON蛋白治疗的未经原发性肿瘤切除的肿瘤组织切片的组织学分析。
对使用溶于PBS缓冲液的QQ-试剂治疗(持续每日治疗18天)的大鼠的9L-肿瘤组织载玻片的H&E染色示出了具有大量血管生成的均质肿瘤细胞。使用抗-VE-钙黏着蛋白抗体对附近的组织载玻片的免疫染色确认了血管生成。在皮下9L细胞植入后第26天处死具有13.5cm3(约15.5g)的肿瘤的该大鼠。相比之下，对使用QQ-SON蛋白治疗(持续每日治疗18天)的大鼠的肿瘤组织载玻片的H&E染色示出了不同的细胞区，包括肿瘤细胞区、结缔组织区和成纤维细胞区。在皮下9L细胞植入后第49天处死该鼠，其肿瘤大小显著减少到0.2cm3(约0.6g)。使用抗-a-原胶原、成纤维细胞标志物、抗体对同一大鼠的附近肿瘤组织载玻片的成纤维细胞区的免疫染色确认了成纤维细胞区(阳性染色)和肿瘤细胞区(阴性染色)。使用抗-GFAP抗体和抗Tuj1抗体对用QQ-SON蛋白治疗(持续每日治疗18天)的同一大鼠的肿瘤组织载玻片的免疫染色显示这两种标志物的阳性染色，形成了神经元细胞形态和神经细胞团。该数据表明所注射的QQ-SON蛋白诱导瞬时9L-piPSC的原位产生，所述瞬时9L-piPSC分化成包括神经元谱系细胞的非癌细胞。
类似地，对用QQ-SON蛋白治疗的小鼠的4T1-肿瘤组织载玻片的H&E染色也示出了脂肪细胞和乳腺导管——其为脂连素和角蛋白5/8/14免疫染色阳性的，表明所注射的QQ-SON蛋白也诱导原发性肿瘤内的4T1-肿瘤细胞原位重编程为4T1-piPSC——其分化成乳腺组织。
实施例24
QQ-SON治疗显著增强经治疗的9L细胞的体内基因组稳定性。
对两只携带皮下9L-肿瘤的大鼠——两者均用QQ-SON蛋白治疗18天——的外植细胞的SKY基因组进行分析。一只大鼠(#12)对QQ-SON治疗表现出主要响应并且肿瘤开始收缩。在肿瘤消失之前，处死该大鼠并收集肿瘤用于外植体和肿瘤组织载玻片。另一只大鼠(#15)对QQ-SON蛋白治疗没有响应并且肿瘤继续增长至达到终点(＞12em3)。也处死该鼠并制备外植体和肿瘤组织载玻片。
来自#15大鼠外植体的细胞迅速生长并在3天内达到汇合。细胞显示出典型的9L-细胞纺锤体形态。然而，来自#12大鼠外植体的细胞生长非常缓慢并且仅在两周后观察到一些具有神经形态的细胞以及一些菌落。对于在#12大鼠中显示神经形态的那些细胞，使用GFAP和Tuj I对肿瘤组织载玻片的免疫染色对这两种标志物显示出阳性染色，但是对于#15大鼠，对这两种标志物为阴性染色。使用β-连环蛋白、CK5/6、E-钙黏着糖蛋白、Lefty、Nodal和Cripto-1的额外的免疫染色对于#12和#15大鼠显示出相反的结果。尽管#12大鼠的肿瘤组织载玻片示出CK5/6、E-钙黏着糖蛋白、Lefty和β-连环蛋白的阳性染色，但是在#15大鼠的肿瘤组织载玻片中观察到阴性染色。有趣的是，Lefty和E-钙黏着糖蛋白以及CK5/6和E-钙黏着糖蛋白在肿瘤组织切片的相同区域中共染色。相比之下，#15大鼠的肿瘤组织载玻片示出对Nodal和Cripto-1的阳性染色，但#12的那些组织切片示出对这两种标志物的阴性染色。这些结果表明在#12大鼠的组织切片中肿瘤细胞转化成非癌细胞，而#15大鼠的组织切片仍然是9L-肿瘤细胞。
为评估外植体细胞的基因组稳定性，进行了分子细胞遗传学分析。对于大鼠#15和大鼠#12的每个外植体收集20个有丝分裂的图像并分析大鼠#15和大鼠#12的平均染色体数目。表4示出了对大鼠#15和大鼠#12染色体畸变的比较。分子细胞遗传学分析表明大鼠#12的35％非克隆性染色体畸变(NCCA)和20％的克隆性染色体畸变(CCA)以及大鼠#15的70％的NCCA和15％CCA(表4)。由于NCCA的频率代表基因组不稳定性水平，而CCA代表相对稳定性，这些数据表明不响应QQ-SON蛋白治疗的肿瘤(大鼠#15)显示出与对QQ-SON治疗显示良好的响应的肿瘤(大鼠#12)的那些相比更高水平的基因组异质性。该结果表明蛋白诱导的原位细胞重编程显著增强经治疗的癌细胞的基因组稳定性，表明恶性癌细胞到非癌细胞的细胞转化。
Figure BDA0002731529550000591
实施例25
通过蛋白诱导的原位细胞重编程介导的QQ-SON诱导的细胞转化的癌症疗法使得携带皮下9L-肿瘤的大鼠和携带晚期4T1的小鼠在手术切除原发性肿瘤后癌症治愈。
进行9L-细胞到Fisher大鼠的皮下植入以产生荷瘤大鼠。肿瘤细胞植入后五天，进行QQ-修饰的SON(QQ-SON)蛋白的每日瘤内注射。还进行溶于PBS的QQ-试剂(QQ-PBS)的适当的对照。在使用QQ-SON蛋白以10μg/只小鼠/天的18天每日瘤内治疗方案后，进行90天的存活实验。在治疗过程中，在所有治疗的大鼠中观察到显著降低的肿瘤生长。在18天的每日治疗之后，50％的经治疗的大鼠随着时间的推移显示出减少的肿瘤体积并且在这些动物中不存在可触及的肿瘤。剩余的经治疗的大鼠显示出显著更慢的肿瘤生长。治疗组的中值存活时间为49±20天(n＝8)，而对照组中的存活时间为21±4天(n＝6)。在第32天、43天和62天，在三只经治疗的大鼠中观察到肿瘤复发，具有45±13天的中值存活时间。复发肿瘤生长非常积极并且在5-7天内达到＞12em3的体积(表5，治疗1)。第四个神经胶质瘤治愈的大鼠保持无瘤超过30个月，没有畸胎瘤形成的证据。
当所述每日肿瘤内治疗方案延长到30天时，在400天的存活实验(n＝8)期间，在头73天内获得100％神经胶质瘤治愈的大鼠。此外，在第73天、78天和92天(中值复发时间：81±8天)观察到三只经治疗的大鼠的肿瘤复发，其远远晚于在仅治疗18天的大鼠中观察到的肿瘤复发。剩余的5只大鼠保持无瘤400天。将具有复发肿瘤的三只大鼠额外治疗30天(每日瘤内注射，10μg/天QQ-SON)。在三只大鼠中，两只具有非常缓慢的进展并且额外存活了66天(在第78天肿瘤发生)或68天(在第92天肿瘤复发)。仅一只大鼠显示出缓慢的肿瘤生长并当肿瘤体积达到12cm3时在第109天(确定为肿瘤复发后36天)被处死。与对照组(n＝6)的21±4天相比，经治疗的大鼠的中值存活时间为280±155天(n＝8)(表5，治疗2)。
为了确保该结果是可重复的，重复上述30天的每日治疗实验并在头79天内获得80％的神经胶质瘤治愈的大鼠。两只大鼠显示出缓慢的肿瘤生长，但是分别在第29天和第48天已经达到12cm3的肿瘤体积(表5，治疗3)。然而，两只神经胶质瘤治愈的大鼠在第79天和第111天显示出肿瘤复发(中值复发时间：95±16天)。将这两只大鼠用QQ-SON蛋白(10μg/天)额外治疗30天。两只大鼠之一显示出缓慢的肿瘤生长并且在第79天肿瘤复发后30天内达到12cm3的体积。另一只大鼠额外存活了69天。经治疗的大鼠的中值存活时间为276±156天(n＝10)，而用QQ-PBS治疗的对照大鼠在肿瘤植入后仅存活23±3天(n＝6)。来自治疗2和治疗3的肿瘤治愈的大鼠目前存活超过15个月，而无肿瘤复发并且不形成畸胎瘤。
Figure BDA0002731529550000611
对于经QQ-PBS和QQ-SON治疗的小鼠，在4T1细胞植入后第18天手术切除原发性肿瘤后的携带晚期4T1-乳腺癌的小鼠中观察到类似的结果。在第5天进行每日肿瘤内QQ-SON蛋白治疗并持续40天。此前，证明了肺转移开始于第7天。在第18天，观察到每只小鼠的MRI可观察到的肺转移病灶。进行250天的存活实验。所得到的数据(表6)表明尽管QQ-PBS对照小鼠死于第25-47天，但是经QQ-SON治疗的小鼠存活更长的时间并且61％(n＝11)的经QQ-SON治疗的小鼠存活整个250天，而无肿瘤复发和畸胎瘤形成(n＝18)，参见图8。MRI结果显示肺转移病灶消失。这些数据证明该QQ-SON诱导的细胞转化癌症疗法的高治疗效力。
Figure BDA0002731529550000612
Figure BDA0002731529550000621
图8是在第18天手术切除原发性4T1-乳腺癌后的携带4T1-乳腺癌的小鼠的Kaplan-Meier存活曲线(250天存活期)。在将4T1-细胞植入到雌性BALB/c小鼠的#4脂肪垫中6天后用QQ-PBS(对照)和QQ-SON蛋白(治疗)治疗这些携带4T1乳腺癌的小鼠。约在第5天，原发性肿瘤是可触及的并在第18天手术切除。通过瘤内注射(5μg/只小鼠/天)和腹膜内注射(25μg/只小鼠/天)每日进行QQ-PBS/QQ-SON治疗。
图8的Kaplan-Meier存活曲线中的第0天为在第18天进行手术时的天数。少数的小鼠由于不完全的肿瘤切除而出现肿瘤复发。将这些小鼠用QQ-SON蛋白或QQ-PBS通过瘤内注射治疗并且也比较它们的存活时间(虚线的存活曲线)。对于没有肿瘤复发的那些小鼠，它们的存活曲线以实线示出。在该整个250天的存活实验之后仍存活的没有肿瘤复发的小鼠被认为是肿瘤治愈的小鼠。已经在61％的经治疗的小鼠种群中实现肿瘤治愈。
因此，证明了QQ-SON诱导的癌细胞在肿瘤内的原位细胞重编程产生在那个组织中分化为不同的非癌细胞的瞬时piPSC。所分化的非癌细胞的类型取决于具体的组织环境。QQ-SON诱导的原位细胞重编程和组织环境诱导的分化之间的该相互作用精确地调节在肿瘤内的瞬时piPSC的产生和诱导的分化，防止了肿瘤和畸胎瘤形成。这种安全的蛋白诱导的原位细胞重编程技术原位生成干细胞，干细胞随后分化为由组织环境诱导的正常细胞以替代病变细胞，用于治疗许多疾病和损伤。
序列
人类SRY(性别决定区Y)-盒2(SOX2)(NM_003106)SEQ ID NO：1(蛋白质)和SEQ IDNO：65(DNA)
Figure BDA0002731529550000631
人类POU 5类同源异型框1(POU5F1)，也称为Oct4(NM_002701)SEQ ID NO：2(蛋白质)和SEQ ID NO：66(DNA)
Figure BDA0002731529550000641
人类Nanog同源异型框(NANOG)(NM_024865)SEQ ID NO：3(蛋白质)和SEQ ID NO：67(DNA)
Figure BDA0002731529550000642
人类的lin-28同源物A(秀丽线虫(C.elegans))(LIN28A)(NM_024674)SEQ ID NO：4(蛋白质)和SEQ ID NO：68(DNA)
Figure BDA0002731529550000651
人类Krueppel样因子4(Klf4)(NP_004226)SEQ ID NO：5(蛋白质)和SEQ ID NO：69(DNA)
Figure BDA0002731529550000652
人类c-MYC(NP_002458)SEQ ID NO：6(蛋白质)和SEQ ID NO：70(DNA)
Figure BDA0002731529550000661
人类GATA结合蛋白4(GATA4)(NM_002052)SEQ ID NO：7(蛋白质)和SEQ ID NO：71(DNA)
Figure BDA0002731529550000662
Figure BDA0002731529550000671
人类心脏和神经嵴表达衍生物2(HAND2)(NM_021973)SEQ ID NO：8(蛋白质)和SEQID NO：72(DNA)
Figure BDA0002731529550000672
人类肌细胞强化因子2C(MEF2C)(NM_001193350)SEQ ID NO：9(蛋白质)和SEQ IDNO：73(DNA)
Figure BDA0002731529550000673
Figure BDA0002731529550000681
人类转录因子TBX5(U80987)SEQ ID NO：10(蛋白质)和SEQ ID NO：74(DNA)
Figure BDA0002731529550000682
人类神经原素3(NEUROG3)(NM_020999.3)SEQ ID NO：11(蛋白质)和SEQ ID NO：75(DNA)
Figure BDA0002731529550000683
人类配对盒4(PAX4)(NM_006193.2)SEQ ID NO：12(蛋白质)和SEQ ID NO：76(DNA)
Figure BDA0002731529550000691
人类胰脏和十二指肠同源异型框1(PDX1)(NM_000209.3)SEQ ID NO：13(蛋白质)和SEQ ID NO：77(DNA)
Figure BDA0002731529550000692
人类SOX9蛋白(1-509)(Z46629.1)SEQ ID NO：14(蛋白质)和SEQ ID NO：78(DNA)
Figure BDA0002731529550000701
人类锌指蛋白SLUG(SLUG)基因(AF084243.1)SEQ ID NO：15(蛋白质)和SEQ IDNO：79(DNA)
Figure BDA0002731529550000702
人类v-maf禽肌腱膜纤维肉瘤致癌基因同源物A(MafA)(NM_201589.3)SEQ ID NO：16(蛋白质)和SEQ ID NO：80(DNA)
Figure BDA0002731529550000711
人类神经原分化1(NEUROD1)(NM_002500.4)SEQ ID NO：17(蛋白质)和SEQ ID NO：81(DNA)
Figure BDA0002731529550000712
人类生肌因子5(MYF5)(NM_005593.2)SEQ ID NO：18(蛋白质)和SEQ ID NO：82(DNA)
Figure BDA0002731529550000721
人类含PR-结构域的蛋白16(PRDM16)(AF294278.1)SEQ ID NO：19(蛋白质)和SEQID NO：83(DNA)
Figure BDA0002731529550000722
Figure BDA0002731529550000731
Figure BDA0002731529550000741
人类配对盒6(PAX6)(NM_001604.5)SEQ ID NO：20(蛋白质)和SEQ ID NO：84(DNA)
Figure BDA0002731529550000742
SEQ ID NO：21：人类HNF1同源异型框A(HNF1A)(NM_000545.5)SEQ ID NO：21(蛋白质)和SEQ ID NO：85(DNA)
Figure BDA0002731529550000743
Figure BDA0002731529550000751
人类叉头盒A3(FOXA3)(NM_004497.2)SEQ ID NO：22(蛋白质)和SEQ ID NO：86(DNA)
Figure BDA0002731529550000752
人类叉头盒A1(FOXA1)(NM_004496.3)SEQ ID NO：23(蛋白质)和SEQ ID NO：87(DNA)
Figure BDA0002731529550000761
Figure BDA0002731529550000762
人人类叉头盒A2(FOXA2)(NM_021784.4)SEQ ID NO：24(蛋白质)和SEQ ID NO：88(DNA)
Figure BDA0002731529550000763
Figure BDA0002731529550000771
SEQ ID NO：25：人类CCAAT/增强子结合蛋白(C/EBP)，α(CEBPA)(NM_001287435.1)SEQ ID NO：25(蛋白质)和SEQ ID NO：89(DNA)
Figure BDA0002731529550000772
人类Spi-1原致癌基因(SPI1)(PU.1)(NM_001080547.1)SEQ ID NO：26(蛋白质)和SEQ ID NO：90(DNA)
Figure BDA0002731529550000773
Figure BDA0002731529550000781
人类POU 3类同源异型框2(POU3F2)(Brn2)(NM_005604.3)SEQ ID NO：27(蛋白质)和SEQ ID NO：91(DNA)
Figure BDA0002731529550000782
Figure BDA0002731529550000783
人人类叉头盒G1(FOXG1)(NM_005249.4)SEQ ID NO：28(蛋白质)和SEQ ID NO：92(DNA)
Figure BDA0002731529550000784
Figure BDA0002731529550000791
人类ASC1蛋白的mRNA(SLC7A10基因)(AJ277731.1)SEQ ID NO：29(蛋白质)和SEQID NO：93(DNA)
Figure BDA0002731529550000792
Figure BDA0002731529550000801
人类achaete-scuteb家族bHLH转录因子1(ASCL1)(NM_004316.3)SEQ ID NO：30(蛋白质)和SEQ ID NO：94(DNA)
Figure BDA0002731529550000802
人类Nurr1基因(AB017586)SEQ ID NO：31(蛋白质)和SEQ ID NO：95(DNA)
Figure BDA0002731529550000803
Figure BDA0002731529550000811
SEQ ID NO：32：人类神经原素2(NEUROG2)(NM_024019)SEQ ID NO：32(蛋白质)和SEQ ID NO：96(DNA)
Figure BDA0002731529550000812
人类LIM同源异型框转录因子1，α(LMX1A)(NM_177398)SEQ ID NO：33(蛋白质)和SEQ ID NO：97(DNA)
Figure BDA0002731529550000813
Figure BDA0002731529550000821
人类HB9同源异型框基因，(U07663)SEQ ID NO：34(蛋白质)和SEQ ID NO：98(DNA)
Figure BDA0002731529550000822
人类LIM同源异型框3(LHX3)(NM_178138)SEQ ID NO：35(蛋白质)和SEQ ID NO：99(DNA)
Figure BDA0002731529550000823
Figure BDA0002731529550000831
人类远端缺失同源异型框2(DLX2)(NM_004405)SEQ ID NO：36(蛋白质)和SEQ IDNO：100(DNA)
Figure BDA0002731529550000832
人类runt相关的转录因子2(RUNX2)(NM_001024630)SEQ ID NO：37(蛋白质)和SEQID NO：101(DNA)
Figure BDA0002731529550000833
Figure BDA0002731529550000841
人类SRY(性别决定区Y)-盒5(SOX5)(NM_006940)SEQ ID NO：38(蛋白质)和SEQ IDNO：102(DNA)
Figure BDA0002731529550000842
Figure BDA0002731529550000851
人类SOX6 mRNA(AF309034)SEQ ID NO：39(蛋白质)和SEQ ID NO：103(DNA)
Figure BDA0002731529550000852
Figure BDA0002731529550000861
人类GATA结合蛋白6(GATA6)(NM_005257)SEQ ID NO：40(蛋白质)和SEQ ID NO：104(DNA)
Figure BDA0002731529550000862
Figure BDA0002731529550000871
人类GATA结合蛋白1(GATA1)(NM_002049)SEQ ID NO：41(蛋白质)和SEQ ID NO：105(DNA)
Figure BDA0002731529550000872
人类Fli-1原致癌基因，ETS转录因子(FLI1)(NM_002017)SEQ ID NO：42(蛋白质)和SEQ ID NO：106(DNA)
Figure BDA0002731529550000873
Figure BDA0002731529550000881
人类红系Kruppel样因子EKLF基因(U37106)SEQ ID NO：43(蛋白质)和SEQ ID NO：107(DNA)
Figure BDA0002731529550000882
人类MyoD(X56677)SEQ ID NO：44(蛋白质)和SEQ ID NO：108(DNA)
Figure BDA0002731529550000891
人类NGFI-A结合蛋白2(EGR1结合蛋白2)(NAB2)(NM_005967)SEQ ID NO：45(蛋白质)和SEQ ID NO：109(DNA)
Figure BDA0002731529550000892
Figure BDA0002731529550000901
人类早期生长响应1(EGR1)(NM_001964)SEQ ID NO：46(蛋白质)和SEQ ID NO：110(DNA)
Figure BDA0002731529550000902
人类独立生长因子1转录阻遏物(GFI1)(NM_005263)SEQ ID NO：47(蛋白质)和SEQID NO：111(DNA)
Figure BDA0002731529550000911
人类配对盒5(PAX5)(NM_016734)SEQ ID NO：48(蛋白质)和SEQ ID NO：112(DNA)
Figure BDA0002731529550000912
人类T细胞特异性T框转录因子T-bet mRNA(AF241243)SEQ ID NO：49(蛋白质)和SEQ ID NO：113(DNA)
Figure BDA0002731529550000921
人类GATA结合蛋白3(GATA3)(NM_001002295)SEQ ID NO：50(蛋白质)和SEQ IDNO：114(DNA)
Figure BDA0002731529550000922
Figure BDA0002731529550000931
人类FOXP3(EF534714)SEQ ID NO：51(蛋白质)和SEQ ID NO：115(DNA)
Figure BDA0002731529550000932
人类孤独受体RORγ(U16997)SEQ ID NO：52(蛋白质)和SEQ ID NO：116(DNA)
Figure BDA0002731529550000941
人类肝细胞核因子4，α(HNF4A)，(NM_178849)SEQ ID NO：53(蛋白质)和SEQ IDNO：117(DNA)
Figure BDA0002731529550000942
Figure BDA0002731529550000951
人类信号传导子及转录激活子Stat5A(U43185)SEQ ID NO：54(蛋白质)和SEQ IDNO：118(DNA)
Figure BDA0002731529550000952
Figure BDA0002731529550000961
人类鲨烯环氧酶(ERG1)mRNA，(AF098865)SEQ ID NO：55(蛋白质)和SEQ ID NO：119(DNA)
Figure BDA0002731529550000962
Figure BDA0002731529550000971
人类ets变体2(ETV2/ER71)，(NM_014209)SEQ ID NO：56(蛋白质)和SEQ ID NO：120(DNA)
Figure BDA0002731529550000972
人类GATA结合蛋白2(GATA2)(NM_001145661)SEQ ID NO：57(蛋白质)和SEQ IDNO：121(DNA)
Figure BDA0002731529550000973
Figure BDA0002731529550000981
具有YRPW基序1(HEY1)的人类hes-相关家族bHLH转录因子(NM_012258)SEQ IDNO：58(蛋白质)和SEQ ID NO：122(DNA)
Figure BDA0002731529550000982
人类Hey2(AB044755)SEQ ID NO：59(蛋白质)和SEQ ID NO：123(DNA)
Figure BDA0002731529550000983
Figure BDA0002731529550000991
人类叉头盒C1(FOXC1)(NM_001453)SEQ ID NO：60(蛋白质)和SEQ ID NO：124(DNA)
Figure BDA0002731529550000992
Figure BDA0002731529550001001
人类叉头盒C2(MFH-1，间质叉头1)(FOXC2)(NM_005251)SEQ ID NO：61(蛋白质)和SEQ ID NO：125(DNA)
Figure BDA0002731529550001002
SEQ ID NO：62：人类SRY(性别决定区Y)-盒7(SOX7)NM_031439SEQ ID NO：62(蛋白质)和SEQ ID NO：126(DNA)
Figure BDA0002731529550001003
Figure BDA0002731529550001011
人类SOX18(AB033888)SEQ ID NO：63(蛋白质)和SEQ ID NO：127(DNA)
Figure BDA0002731529550001012
本说明书提及的任何专利或出版物都以引用的方式纳入本文，其程度如同每一个单独的出版物被具体地并且单独地被指明以引用的方式纳入本文一样。于2013年10月25日提交的序列号为61/895，562的美国临时专利申请以引用的方式纳入本文。
本文所述的组合物和方法目前代表优选的实施方案，其为示例性的且不意欲对本发明的范围进行限制。本领域技术人员会了解其中的改变和其他用途。可在不脱离如权利要求中所述的本发明的范围的情况下进行这类改变和其他用途。
序列表
<110> 韦恩州立大学
亨利福特医疗集团
<120> 与通过蛋白诱导的体内细胞重编程的细胞转化相关的方法、系统和组合物
<130> WAY-10252/47
<150> 61/895,562
<151> 2013-10-25
<160> 127
<170> PatentIn version 3.5
<210> 1
<211> 317
<212> PRT
<213> 人类
<400> 1
Met Tyr Asn Met Met Glu Thr Glu Leu Lys Pro Pro Gly Pro Gln Gln
1 5 10 15
Thr Ser Gly Gly Gly Gly Gly Asn Ser Thr Ala Ala Ala Ala Gly Gly
20 25 30
Asn Gln Lys Asn Ser Pro Asp Arg Val Lys Arg Pro Met Asn Ala Phe
35 40 45
Met Val Trp Ser Arg Gly Gln Arg Arg Lys Met Ala Gln Glu Asn Pro
50 55 60
Lys Met His Asn Ser Glu Ile Ser Lys Arg Leu Gly Ala Glu Trp Lys
65 70 75 80
Leu Leu Ser Glu Thr Glu Lys Arg Pro Phe Ile Asp Glu Ala Lys Arg
85 90 95
Leu Arg Ala Leu His Met Lys Glu His Pro Asp Tyr Lys Tyr Arg Pro
100 105 110
Arg Arg Lys Thr Lys Thr Leu Met Lys Lys Asp Lys Tyr Thr Leu Pro
115 120 125
Gly Gly Leu Leu Ala Pro Gly Gly Asn Ser Met Ala Ser Gly Val Gly
130 135 140
Val Gly Ala Gly Leu Gly Ala Gly Val Asn Gln Arg Met Asp Ser Tyr
145 150 155 160
Ala His Met Asn Gly Trp Ser Asn Gly Ser Tyr Ser Met Met Gln Asp
165 170 175
Gln Leu Gly Tyr Pro Gln His Pro Gly Leu Asn Ala His Gly Ala Ala
180 185 190
Gln Met Gln Pro Met His Arg Tyr Asp Val Ser Ala Leu Gln Tyr Asn
195 200 205
Ser Met Thr Ser Ser Gln Thr Tyr Met Asn Gly Ser Pro Thr Tyr Ser
210 215 220
Met Ser Tyr Ser Gln Gln Gly Thr Pro Gly Met Ala Leu Gly Ser Met
225 230 235 240
Gly Ser Val Val Lys Ser Glu Ala Ser Ser Ser Pro Pro Val Val Thr
245 250 255
Ser Ser Ser His Ser Arg Ala Pro Cys Gln Ala Gly Asp Leu Arg Asp
260 265 270
Met Ile Ser Met Tyr Leu Pro Gly Ala Glu Val Pro Glu Pro Ala Ala
275 280 285
Pro Ser Arg Leu His Met Ser Gln His Tyr Gln Ser Gly Pro Val Pro
290 295 300
Gly Thr Ala Ile Asn Gly Thr Leu Pro Leu Ser His Met
305 310 315
<210> 2
<211> 360
<212> PRT
<213> 人类
<400> 2
Met Ala Gly His Leu Ala Ser Asp Phe Ala Phe Ser Pro Pro Pro Gly
1 5 10 15
Gly Gly Gly Asp Gly Pro Gly Gly Pro Glu Pro Gly Trp Val Asp Pro
20 25 30
Arg Thr Trp Leu Ser Phe Gln Gly Pro Pro Gly Gly Pro Gly Ile Gly
35 40 45
Pro Gly Val Gly Pro Gly Ser Glu Val Trp Gly Ile Pro Pro Cys Pro
50 55 60
Pro Pro Tyr Glu Phe Cys Gly Gly Met Ala Tyr Cys Gly Pro Gln Val
65 70 75 80
Gly Val Gly Leu Val Pro Gln Gly Gly Leu Glu Thr Ser Gln Pro Glu
85 90 95
Gly Glu Ala Gly Val Gly Val Glu Ser Asn Ser Asp Gly Ala Ser Pro
100 105 110
Glu Pro Cys Thr Val Thr Pro Gly Ala Val Lys Leu Glu Lys Glu Lys
115 120 125
Leu Glu Gln Asn Pro Glu Glu Ser Gln Asp Ile Lys Ala Leu Gln Lys
130 135 140
Glu Leu Glu Gln Phe Ala Lys Leu Leu Lys Gln Lys Arg Ile Thr Leu
145 150 155 160
Gly Tyr Thr Gln Ala Asp Val Gly Leu Thr Leu Gly Val Leu Phe Gly
165 170 175
Lys Val Phe Ser Gln Thr Thr Ile Cys Arg Phe Glu Ala Leu Gln Leu
180 185 190
Ser Phe Lys Asn Met Cys Lys Leu Arg Pro Leu Leu Gln Lys Trp Val
195 200 205
Glu Glu Ala Asp Asn Asn Glu Asn Leu Gln Glu Ile Cys Lys Ala Glu
210 215 220
Thr Leu Val Gln Ala Arg Lys Arg Lys Arg Thr Ser Ile Glu Asn Arg
225 230 235 240
Val Arg Gly Asn Leu Glu Asn Leu Phe Leu Gln Cys Pro Lys Pro Thr
245 250 255
Leu Gln Gln Ile Ser His Ile Ala Gln Gln Leu Gly Leu Glu Lys Asp
260 265 270
Val Val Arg Val Trp Phe Cys Asn Arg Arg Gln Lys Gly Lys Arg Ser
275 280 285
Ser Ser Asp Tyr Ala Gln Arg Glu Asp Phe Glu Ala Ala Gly Ser Pro
290 295 300
Phe Ser Gly Gly Pro Val Ser Phe Pro Leu Ala Pro Gly Pro His Phe
305 310 315 320
Gly Thr Pro Gly Tyr Gly Ser Pro His Phe Thr Ala Leu Tyr Ser Ser
325 330 335
Val Pro Phe Pro Glu Gly Glu Ala Phe Pro Pro Val Ser Val Thr Thr
340 345 350
Leu Gly Ser Pro Met His Ser Asn
355 360
<210> 3
<211> 305
<212> PRT
<213> 人类
<400> 3
Met Ser Val Asp Pro Ala Cys Pro Gln Ser Leu Pro Cys Phe Glu Ala
1 5 10 15
Ser Asp Cys Lys Glu Ser Ser Pro Met Pro Val Ile Cys Gly Pro Glu
20 25 30
Glu Asn Tyr Pro Ser Leu Gln Met Ser Ser Ala Glu Met Pro His Thr
35 40 45
Glu Thr Val Ser Pro Leu Pro Ser Ser Met Asp Leu Leu Ile Gln Asp
50 55 60
Ser Pro Asp Ser Ser Thr Ser Pro Lys Gly Lys Gln Pro Thr Ser Ala
65 70 75 80
Glu Lys Ser Val Ala Lys Lys Glu Asp Lys Val Pro Val Lys Lys Gln
85 90 95
Lys Thr Arg Thr Val Phe Ser Ser Thr Gln Leu Cys Val Leu Asn Asp
100 105 110
Arg Phe Gln Arg Gln Lys Tyr Leu Ser Leu Gln Gln Met Gln Glu Leu
115 120 125
Ser Asn Ile Leu Asn Leu Ser Tyr Lys Gln Val Lys Thr Trp Phe Gln
130 135 140
Asn Gln Arg Met Lys Ser Lys Arg Trp Gln Lys Asn Asn Trp Pro Lys
145 150 155 160
Asn Ser Asn Gly Val Thr Gln Lys Ala Ser Ala Pro Thr Tyr Pro Ser
165 170 175
Leu Tyr Ser Ser Tyr His Gln Gly Cys Leu Val Asn Pro Thr Gly Asn
180 185 190
Leu Pro Met Trp Ser Asn Gln Thr Trp Asn Asn Ser Thr Trp Ser Asn
195 200 205
Gln Thr Gln Asn Ile Gln Ser Trp Ser Asn His Ser Trp Asn Thr Gln
210 215 220
Thr Trp Cys Thr Gln Ser Trp Asn Asn Gln Ala Trp Asn Ser Pro Phe
225 230 235 240
Tyr Asn Cys Gly Glu Glu Ser Leu Gln Ser Cys Met Gln Phe Gln Pro
245 250 255
Asn Ser Pro Ala Ser Asp Leu Glu Ala Ala Leu Glu Ala Ala Gly Glu
260 265 270
Gly Leu Asn Val Ile Gln Gln Thr Thr Arg Tyr Phe Ser Thr Pro Gln
275 280 285
Thr Met Asp Leu Phe Leu Asn Tyr Ser Met Asn Met Gln Pro Glu Asp
290 295 300
Val
305
<210> 4
<211> 209
<212> PRT
<213> 人类
<400> 4
Met Gly Ser Val Ser Asn Gln Gln Phe Ala Gly Gly Cys Ala Lys Ala
1 5 10 15
Ala Glu Glu Ala Pro Glu Glu Ala Pro Glu Asp Ala Ala Arg Ala Ala
20 25 30
Asp Glu Pro Gln Leu Leu His Gly Ala Gly Ile Cys Lys Trp Phe Asn
35 40 45
Val Arg Met Gly Phe Gly Phe Leu Ser Met Thr Ala Arg Ala Gly Val
50 55 60
Ala Leu Asp Pro Pro Val Asp Val Phe Val His Gln Ser Lys Leu His
65 70 75 80
Met Glu Gly Phe Arg Ser Leu Lys Glu Gly Glu Ala Val Glu Phe Thr
85 90 95
Phe Lys Lys Ser Ala Lys Gly Leu Glu Ser Ile Arg Val Thr Gly Pro
100 105 110
Gly Gly Val Phe Cys Ile Gly Ser Glu Arg Arg Pro Lys Gly Lys Ser
115 120 125
Met Gln Lys Arg Arg Ser Lys Gly Asp Arg Cys Tyr Asn Cys Gly Gly
130 135 140
Leu Asp His His Ala Lys Glu Cys Lys Leu Pro Pro Gln Pro Lys Lys
145 150 155 160
Cys His Phe Cys Gln Ser Ile Ser His Met Val Ala Ser Cys Pro Leu
165 170 175
Lys Ala Gln Gln Gly Pro Ser Ala Gln Gly Lys Pro Thr Tyr Phe Arg
180 185 190
Glu Glu Glu Glu Glu Ile His Ser Pro Thr Leu Leu Pro Glu Ala Gln
195 200 205
Asn
<210> 5
<211> 479
<212> PRT
<213> 人类
<400> 5
Met Arg Gln Pro Pro Gly Glu Ser Asp Met Ala Val Ser Asp Ala Leu
1 5 10 15
Leu Pro Ser Phe Ser Thr Phe Ala Ser Gly Pro Ala Gly Arg Glu Lys
20 25 30
Thr Leu Arg Gln Ala Gly Ala Pro Asn Asn Arg Trp Arg Glu Glu Leu
35 40 45
Ser His Met Lys Arg Leu Pro Pro Val Leu Pro Gly Arg Pro Tyr Asp
50 55 60
Leu Ala Ala Ala Thr Val Ala Thr Asp Leu Glu Ser Gly Gly Ala Gly
65 70 75 80
Ala Ala Cys Gly Gly Ser Asn Leu Ala Pro Leu Pro Arg Arg Glu Thr
85 90 95
Glu Glu Phe Asn Asp Leu Leu Asp Leu Asp Phe Ile Leu Ser Asn Ser
100 105 110
Leu Thr His Pro Pro Glu Ser Val Ala Ala Thr Val Ser Ser Ser Ala
115 120 125
Ser Ala Ser Ser Ser Ser Ser Pro Ser Ser Ser Gly Pro Ala Ser Ala
130 135 140
Pro Ser Thr Cys Ser Phe Thr Tyr Pro Ile Arg Ala Gly Asn Asp Pro
145 150 155 160
Gly Val Ala Pro Gly Gly Thr Gly Gly Gly Leu Leu Tyr Gly Arg Glu
165 170 175
Ser Ala Pro Pro Pro Thr Ala Pro Phe Asn Leu Ala Asp Ile Asn Asp
180 185 190
Val Ser Pro Ser Gly Gly Phe Val Ala Glu Leu Leu Arg Pro Glu Leu
195 200 205
Asp Pro Val Tyr Ile Pro Pro Gln Gln Pro Gln Pro Pro Gly Gly Gly
210 215 220
Leu Met Gly Lys Phe Val Leu Lys Ala Ser Leu Ser Ala Pro Gly Ser
225 230 235 240
Glu Tyr Gly Ser Pro Ser Val Ile Ser Val Ser Lys Gly Ser Pro Asp
245 250 255
Gly Ser His Pro Val Val Val Ala Pro Tyr Asn Gly Gly Pro Pro Arg
260 265 270
Thr Cys Pro Lys Ile Lys Gln Glu Ala Val Ser Ser Cys Thr His Leu
275 280 285
Gly Ala Gly Pro Pro Leu Ser Asn Gly His Arg Pro Ala Ala His Asp
290 295 300
Phe Pro Leu Gly Arg Gln Leu Pro Ser Arg Thr Thr Pro Thr Leu Gly
305 310 315 320
Leu Glu Glu Val Leu Ser Ser Arg Asp Cys His Pro Ala Leu Pro Leu
325 330 335
Pro Pro Gly Phe His Pro His Pro Gly Pro Asn Tyr Pro Ser Phe Leu
340 345 350
Pro Asp Gln Met Gln Pro Gln Val Pro Pro Leu His Tyr Gln Glu Leu
355 360 365
Met Pro Pro Gly Ser Cys Met Pro Glu Glu Pro Lys Pro Lys Arg Gly
370 375 380
Arg Arg Ser Trp Pro Arg Lys Arg Thr Ala Thr His Thr Cys Asp Tyr
385 390 395 400
Ala Gly Cys Gly Lys Thr Tyr Thr Lys Ser Ser His Leu Lys Ala His
405 410 415
Leu Arg Thr His Thr Gly Glu Lys Pro Tyr His Cys Asp Trp Asp Gly
420 425 430
Cys Gly Trp Lys Phe Ala Arg Ser Asp Glu Leu Thr Arg His Tyr Arg
435 440 445
Lys His Thr Gly His Arg Pro Phe Gln Cys Gln Lys Cys Asp Arg Ala
450 455 460
Phe Ser Arg Ser Asp His Leu Ala Leu His Met Lys Arg His Phe
465 470 475
<210> 6
<211> 454
<212> PRT
<213> 人类
<400> 6
Met Asp Phe Phe Arg Val Val Glu Asn Gln Gln Pro Pro Ala Thr Met
1 5 10 15
Pro Leu Asn Val Ser Phe Thr Asn Arg Asn Tyr Asp Leu Asp Tyr Asp
20 25 30
Ser Val Gln Pro Tyr Phe Tyr Cys Asp Glu Glu Glu Asn Phe Tyr Gln
35 40 45
Gln Gln Gln Gln Ser Glu Leu Gln Pro Pro Ala Pro Ser Glu Asp Ile
50 55 60
Trp Lys Lys Phe Glu Leu Leu Pro Thr Pro Pro Leu Ser Pro Ser Arg
65 70 75 80
Arg Ser Gly Leu Cys Ser Pro Ser Tyr Val Ala Val Thr Pro Phe Ser
85 90 95
Leu Arg Gly Asp Asn Asp Gly Gly Gly Gly Ser Phe Ser Thr Ala Asp
100 105 110
Gln Leu Glu Met Val Thr Glu Leu Leu Gly Gly Asp Met Val Asn Gln
115 120 125
Ser Phe Ile Cys Asp Pro Asp Asp Glu Thr Phe Ile Lys Asn Ile Ile
130 135 140
Ile Gln Asp Cys Met Trp Ser Gly Phe Ser Ala Ala Ala Lys Leu Val
145 150 155 160
Ser Glu Lys Leu Ala Ser Tyr Gln Ala Ala Arg Lys Asp Ser Gly Ser
165 170 175
Pro Asn Pro Ala Arg Gly His Ser Val Cys Ser Thr Ser Ser Leu Tyr
180 185 190
Leu Gln Asp Leu Ser Ala Ala Ala Ser Glu Cys Ile Asp Pro Ser Val
195 200 205
Val Phe Pro Tyr Pro Leu Asn Asp Ser Ser Ser Pro Lys Ser Cys Ala
210 215 220
Ser Gln Asp Ser Ser Ala Phe Ser Pro Ser Ser Asp Ser Leu Leu Ser
225 230 235 240
Ser Thr Glu Ser Ser Pro Gln Gly Ser Pro Glu Pro Leu Val Leu His
245 250 255
Glu Glu Thr Pro Pro Thr Thr Ser Ser Asp Ser Glu Glu Glu Gln Glu
260 265 270
Asp Glu Glu Glu Ile Asp Val Val Ser Val Glu Lys Arg Gln Ala Pro
275 280 285
Gly Lys Arg Ser Glu Ser Gly Ser Pro Ser Ala Gly Gly His Ser Lys
290 295 300
Pro Pro His Ser Pro Leu Val Leu Lys Arg Cys His Val Ser Thr His
305 310 315 320
Gln His Asn Tyr Ala Ala Pro Pro Ser Thr Arg Lys Asp Tyr Pro Ala
325 330 335
Ala Lys Arg Val Lys Leu Asp Ser Val Arg Val Leu Arg Gln Ile Ser
340 345 350
Asn Asn Arg Lys Cys Thr Ser Pro Arg Ser Ser Asp Thr Glu Glu Asn
355 360 365
Val Lys Arg Arg Thr His Asn Val Leu Glu Arg Gln Arg Arg Asn Glu
370 375 380
Leu Lys Arg Ser Phe Phe Ala Leu Arg Asp Gln Ile Pro Glu Leu Glu
385 390 395 400
Asn Asn Glu Lys Ala Pro Lys Val Val Ile Leu Lys Lys Ala Thr Ala
405 410 415
Tyr Ile Leu Ser Val Gln Ala Glu Glu Gln Lys Leu Ile Ser Glu Glu
420 425 430
Asp Leu Leu Arg Lys Arg Arg Glu Gln Leu Lys His Lys Leu Glu Gln
435 440 445
Leu Arg Asn Ser Cys Ala
450
<210> 7
<211> 442
<212> PRT
<213> 人类
<400> 7
Met Tyr Gln Ser Leu Ala Met Ala Ala Asn His Gly Pro Pro Pro Gly
1 5 10 15
Ala Tyr Glu Ala Gly Gly Pro Gly Ala Phe Met His Gly Ala Gly Ala
20 25 30
Ala Ser Ser Pro Val Tyr Val Pro Thr Pro Arg Val Pro Ser Ser Val
35 40 45
Leu Gly Leu Ser Tyr Leu Gln Gly Gly Gly Ala Gly Ser Ala Ser Gly
50 55 60
Gly Ala Ser Gly Gly Ser Ser Gly Gly Ala Ala Ser Gly Ala Gly Pro
65 70 75 80
Gly Thr Gln Gln Gly Ser Pro Gly Trp Ser Gln Ala Gly Ala Asp Gly
85 90 95
Ala Ala Tyr Thr Pro Pro Pro Val Ser Pro Arg Phe Ser Phe Pro Gly
100 105 110
Thr Thr Gly Ser Leu Ala Ala Ala Ala Ala Ala Ala Ala Ala Arg Glu
115 120 125
Ala Ala Ala Tyr Ser Ser Gly Gly Gly Ala Ala Gly Ala Gly Leu Ala
130 135 140
Gly Arg Glu Gln Tyr Gly Arg Ala Gly Phe Ala Gly Ser Tyr Ser Ser
145 150 155 160
Pro Tyr Pro Ala Tyr Met Ala Asp Val Gly Ala Ser Trp Ala Ala Ala
165 170 175
Ala Ala Ala Ser Ala Gly Pro Phe Asp Ser Pro Val Leu His Ser Leu
180 185 190
Pro Gly Arg Ala Asn Pro Ala Ala Arg His Pro Asn Leu Asp Met Phe
195 200 205
Asp Asp Phe Ser Glu Gly Arg Glu Cys Val Asn Cys Gly Ala Met Ser
210 215 220
Thr Pro Leu Trp Arg Arg Asp Gly Thr Gly His Tyr Leu Cys Asn Ala
225 230 235 240
Cys Gly Leu Tyr His Lys Met Asn Gly Ile Asn Arg Pro Leu Ile Lys
245 250 255
Pro Gln Arg Arg Leu Ser Ala Ser Arg Arg Val Gly Leu Ser Cys Ala
260 265 270
Asn Cys Gln Thr Thr Thr Thr Thr Leu Trp Arg Arg Asn Ala Glu Gly
275 280 285
Glu Pro Val Cys Asn Ala Cys Gly Leu Tyr Met Lys Leu His Gly Val
290 295 300
Pro Arg Pro Leu Ala Met Arg Lys Glu Gly Ile Gln Thr Arg Lys Arg
305 310 315 320
Lys Pro Lys Asn Leu Asn Lys Ser Lys Thr Pro Ala Ala Pro Ser Gly
325 330 335
Ser Glu Ser Leu Pro Pro Ala Ser Gly Ala Ser Ser Asn Ser Ser Asn
340 345 350
Ala Thr Thr Ser Ser Ser Glu Glu Met Arg Pro Ile Lys Thr Glu Pro
355 360 365
Gly Leu Ser Ser His Tyr Gly His Ser Ser Ser Val Ser Gln Thr Phe
370 375 380
Ser Val Ser Ala Met Ser Gly His Gly Pro Ser Ile His Pro Val Leu
385 390 395 400
Ser Ala Leu Lys Leu Ser Pro Gln Gly Tyr Ala Ser Pro Val Ser Gln
405 410 415
Ser Pro Gln Thr Ser Ser Lys Gln Asp Ser Trp Asn Ser Leu Val Leu
420 425 430
Ala Asp Ser His Gly Asp Ile Ile Thr Ala
435 440
<210> 8
<211> 217
<212> PRT
<213> 人类
<400> 8
Met Ser Leu Val Gly Gly Phe Pro His His Pro Val Val His His Glu
1 5 10 15
Gly Tyr Pro Phe Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
20 25 30
Ser Arg Cys Ser His Glu Glu Asn Pro Tyr Phe His Gly Trp Leu Ile
35 40 45
Gly His Pro Glu Met Ser Pro Pro Asp Tyr Ser Met Ala Leu Ser Tyr
50 55 60
Ser Pro Glu Tyr Ala Ser Gly Ala Ala Gly Leu Asp His Ser His Tyr
65 70 75 80
Gly Gly Val Pro Pro Gly Ala Gly Pro Pro Gly Leu Gly Gly Pro Arg
85 90 95
Pro Val Lys Arg Arg Gly Thr Ala Asn Arg Lys Glu Arg Arg Arg Thr
100 105 110
Gln Ser Ile Asn Ser Ala Phe Ala Glu Leu Arg Glu Cys Ile Pro Asn
115 120 125
Val Pro Ala Asp Thr Lys Leu Ser Lys Ile Lys Thr Leu Arg Leu Ala
130 135 140
Thr Ser Tyr Ile Ala Tyr Leu Met Asp Leu Leu Ala Lys Asp Asp Gln
145 150 155 160
Asn Gly Glu Ala Glu Ala Phe Lys Ala Glu Ile Lys Lys Thr Asp Val
165 170 175
Lys Glu Glu Lys Arg Lys Lys Glu Leu Asn Glu Ile Leu Lys Ser Thr
180 185 190
Val Ser Ser Asn Asp Lys Lys Thr Lys Gly Arg Thr Gly Trp Pro Gln
195 200 205
His Val Trp Ala Leu Glu Leu Lys Gln
210 215
<210> 9
<211> 473
<212> PRT
<213> 人类
<400> 9
Met Gly Arg Lys Lys Ile Gln Ile Thr Arg Ile Met Asp Glu Arg Asn
1 5 10 15
Arg Gln Val Thr Phe Thr Lys Arg Lys Phe Gly Leu Met Lys Lys Ala
20 25 30
Tyr Glu Leu Ser Val Leu Cys Asp Cys Glu Ile Ala Leu Ile Ile Phe
35 40 45
Asn Ser Thr Asn Lys Leu Phe Gln Tyr Ala Ser Thr Asp Met Asp Lys
50 55 60
Val Leu Leu Lys Tyr Thr Glu Tyr Asn Glu Pro His Glu Ser Arg Thr
65 70 75 80
Asn Ser Asp Ile Val Glu Thr Leu Arg Lys Lys Gly Leu Asn Gly Cys
85 90 95
Asp Ser Pro Asp Pro Asp Ala Asp Asp Ser Val Gly His Ser Pro Glu
100 105 110
Ser Glu Asp Lys Tyr Arg Lys Ile Asn Glu Asp Ile Asp Leu Met Ile
115 120 125
Ser Arg Gln Arg Leu Cys Ala Val Pro Pro Pro Asn Phe Glu Met Pro
130 135 140
Val Ser Ile Pro Val Ser Ser His Asn Ser Leu Val Tyr Ser Asn Pro
145 150 155 160
Val Ser Ser Leu Gly Asn Pro Asn Leu Leu Pro Leu Ala His Pro Ser
165 170 175
Leu Gln Arg Asn Ser Met Ser Pro Gly Val Thr His Arg Pro Pro Ser
180 185 190
Ala Gly Asn Thr Gly Gly Leu Met Gly Gly Asp Leu Thr Ser Gly Ala
195 200 205
Gly Thr Ser Ala Gly Asn Gly Tyr Gly Asn Pro Arg Asn Ser Pro Gly
210 215 220
Leu Leu Val Ser Pro Gly Asn Leu Asn Lys Asn Met Gln Ala Lys Ser
225 230 235 240
Pro Pro Pro Met Asn Leu Gly Met Asn Asn Arg Lys Pro Asp Leu Arg
245 250 255
Val Leu Ile Pro Pro Gly Ser Lys Asn Thr Met Pro Ser Val Ser Glu
260 265 270
Asp Val Asp Leu Leu Leu Asn Gln Arg Ile Asn Asn Ser Gln Ser Ala
275 280 285
Gln Ser Leu Ala Thr Pro Val Val Ser Val Ala Thr Pro Thr Leu Pro
290 295 300
Gly Gln Gly Met Gly Gly Tyr Pro Ser Ala Ile Ser Thr Thr Tyr Gly
305 310 315 320
Thr Glu Tyr Ser Leu Ser Ser Ala Asp Leu Ser Ser Leu Ser Gly Phe
325 330 335
Asn Thr Ala Ser Ala Leu His Leu Gly Ser Val Thr Gly Trp Gln Gln
340 345 350
Gln His Leu His Asn Met Pro Pro Ser Ala Leu Ser Gln Leu Gly Ala
355 360 365
Cys Thr Ser Thr His Leu Ser Gln Ser Ser Asn Leu Ser Leu Pro Ser
370 375 380
Thr Gln Ser Leu Asn Ile Lys Ser Glu Pro Val Ser Pro Pro Arg Asp
385 390 395 400
Arg Thr Thr Thr Pro Ser Arg Tyr Pro Gln His Thr Arg His Glu Ala
405 410 415
Gly Arg Ser Pro Val Asp Ser Leu Ser Ser Cys Ser Ser Ser Tyr Asp
420 425 430
Gly Ser Asp Arg Glu Asp His Arg Asn Glu Phe His Ser Pro Ile Gly
435 440 445
Leu Thr Arg Pro Ser Pro Asp Glu Arg Glu Ser Pro Ser Val Lys Arg
450 455 460
Met Arg Leu Ser Glu Gly Trp Ala Thr
465 470
<210> 10
<211> 349
<212> PRT
<213> 人类
<400> 10
Met Ala Asp Ala Asp Glu Gly Phe Gly Leu Ala His Thr Pro Leu Glu
1 5 10 15
Pro Asp Ala Lys Asp Leu Pro Cys Asp Ser Lys Pro Glu Ser Ala Leu
20 25 30
Gly Ala Pro Ser Lys Ser Pro Ser Ser Pro Gln Ala Ala Phe Thr Gln
35 40 45
Gln Gly Met Glu Gly Ile Lys Val Phe Leu His Glu Arg Glu Leu Trp
50 55 60
Leu Lys Phe His Glu Val Gly Thr Glu Met Ile Ile Thr Lys Ala Gly
65 70 75 80
Arg Arg Met Phe Pro Ser Tyr Lys Val Lys Val Thr Gly Leu Asn Pro
85 90 95
Lys Thr Lys Tyr Ile Leu Leu Met Asp Ile Val Pro Ala Asp Asp His
100 105 110
Arg Tyr Lys Phe Ala Asp Asn Lys Trp Ser Val Thr Gly Lys Ala Glu
115 120 125
Pro Ala Met Pro Gly Arg Leu Tyr Val His Pro Asp Ser Pro Ala Thr
130 135 140
Gly Ala His Trp Met Arg Gln Leu Val Ser Phe Gln Lys Leu Lys Leu
145 150 155 160
Thr Asn Asn His Leu Asp Pro Phe Gly His Ile Ile Leu Asn Ser Met
165 170 175
His Lys Tyr Gln Pro Arg Leu His Ile Val Lys Ala Asp Glu Asn Asn
180 185 190
Gly Phe Gly Ser Lys Asn Thr Ala Phe Cys Thr His Val Phe Pro Glu
195 200 205
Thr Ala Phe Ile Ala Val Thr Ser Tyr Gln Asn His Lys Ile Thr Gln
210 215 220
Leu Lys Ile Glu Asn Asn Pro Phe Ala Lys Gly Phe Arg Gly Ser Asp
225 230 235 240
Asp Met Glu Leu His Arg Met Ser Arg Met Gln Ser Lys Glu Tyr Pro
245 250 255
Val Val Pro Arg Ser Thr Val Arg Gln Lys Val Ala Ser Asn His Ser
260 265 270
Pro Phe Ser Ser Glu Ser Arg Ala Leu Ser Thr Ser Ser Asn Leu Gly
275 280 285
Ser Gln Tyr Gln Cys Glu Asn Gly Val Ser Gly Pro Ser Gln Asp Leu
290 295 300
Leu Pro Pro Pro Asn Pro Tyr Pro Leu Pro Gln Glu His Ser Gln Ile
305 310 315 320
Tyr His Cys Thr Lys Arg Lys Gly Glu Cys Asp His Pro Trp Ser Ile
325 330 335
Cys Phe Leu Ser Tyr Leu Phe Leu Ser Leu Gly Trp Gly
340 345
<210> 11
<211> 214
<212> PRT
<213> 人类
<400> 11
Met Thr Pro Gln Pro Ser Gly Ala Pro Thr Val Gln Val Thr Arg Glu
1 5 10 15
Thr Glu Arg Ser Phe Pro Arg Ala Ser Glu Asp Glu Val Thr Cys Pro
20 25 30
Thr Ser Ala Pro Pro Ser Pro Thr Arg Thr Arg Gly Asn Cys Ala Glu
35 40 45
Ala Glu Glu Gly Gly Cys Arg Gly Ala Pro Arg Lys Leu Arg Ala Arg
50 55 60
Arg Gly Gly Arg Ser Arg Pro Lys Ser Glu Leu Ala Leu Ser Lys Gln
65 70 75 80
Arg Arg Ser Arg Arg Lys Lys Ala Asn Asp Arg Glu Arg Asn Arg Met
85 90 95
His Asn Leu Asn Ser Ala Leu Asp Ala Leu Arg Gly Val Leu Pro Thr
100 105 110
Phe Pro Asp Asp Ala Lys Leu Thr Lys Ile Glu Thr Leu Arg Phe Ala
115 120 125
His Asn Tyr Ile Trp Ala Leu Thr Gln Thr Leu Arg Ile Ala Asp His
130 135 140
Ser Leu Tyr Ala Leu Glu Pro Pro Ala Pro His Cys Gly Glu Leu Gly
145 150 155 160
Ser Pro Gly Gly Ser Pro Gly Asp Trp Gly Ser Leu Tyr Ser Pro Val
165 170 175
Ser Gln Ala Gly Ser Leu Ser Pro Ala Ala Ser Leu Glu Glu Arg Pro
180 185 190
Gly Leu Leu Gly Ala Thr Phe Ser Ala Cys Leu Ser Pro Gly Ser Leu
195 200 205
Ala Phe Ser Asp Phe Leu
210
<210> 12
<211> 343
<212> PRT
<213> 人类
<400> 12
Met Asn Gln Leu Gly Gly Leu Phe Val Asn Gly Arg Pro Leu Pro Leu
1 5 10 15
Asp Thr Arg Gln Gln Ile Val Arg Leu Ala Val Ser Gly Met Arg Pro
20 25 30
Cys Asp Ile Ser Arg Ile Leu Lys Val Ser Asn Gly Cys Val Ser Lys
35 40 45
Ile Leu Gly Arg Tyr Tyr Arg Thr Gly Val Leu Glu Pro Lys Gly Ile
50 55 60
Gly Gly Ser Lys Pro Arg Leu Ala Thr Pro Pro Val Val Ala Arg Ile
65 70 75 80
Ala Gln Leu Lys Gly Glu Cys Pro Ala Leu Phe Ala Trp Glu Ile Gln
85 90 95
Arg Gln Leu Cys Ala Glu Gly Leu Cys Thr Gln Asp Lys Thr Pro Ser
100 105 110
Val Ser Ser Ile Asn Arg Val Leu Arg Ala Leu Gln Glu Asp Gln Gly
115 120 125
Leu Pro Cys Thr Arg Leu Arg Ser Pro Ala Val Leu Ala Pro Ala Val
130 135 140
Leu Thr Pro His Ser Gly Ser Glu Thr Pro Arg Gly Thr His Pro Gly
145 150 155 160
Thr Gly His Arg Asn Arg Thr Ile Phe Ser Pro Ser Gln Ala Glu Ala
165 170 175
Leu Glu Lys Glu Phe Gln Arg Gly Gln Tyr Pro Asp Ser Val Ala Arg
180 185 190
Gly Lys Leu Ala Thr Ala Thr Ser Leu Pro Glu Asp Thr Val Arg Val
195 200 205
Trp Phe Ser Asn Arg Arg Ala Lys Trp Arg Arg Gln Glu Lys Leu Lys
210 215 220
Trp Glu Met Gln Leu Pro Gly Ala Ser Gln Gly Leu Thr Val Pro Arg
225 230 235 240
Val Ala Pro Gly Ile Ile Ser Ala Gln Gln Ser Pro Gly Ser Val Pro
245 250 255
Thr Ala Ala Leu Pro Ala Leu Glu Pro Leu Gly Pro Ser Cys Tyr Gln
260 265 270
Leu Cys Trp Ala Thr Ala Pro Glu Arg Cys Leu Ser Asp Thr Pro Pro
275 280 285
Lys Ala Cys Leu Lys Pro Cys Trp Gly His Leu Pro Pro Gln Pro Asn
290 295 300
Ser Leu Asp Ser Gly Leu Leu Cys Leu Pro Cys Pro Ser Ser His Cys
305 310 315 320
His Leu Ala Ser Leu Ser Gly Ser Gln Ala Leu Leu Trp Pro Gly Cys
325 330 335
Pro Leu Leu Tyr Gly Leu Glu
340
<210> 13
<211> 283
<212> PRT
<213> 人类
<400> 13
Met Asn Gly Glu Glu Gln Tyr Tyr Ala Ala Thr Gln Leu Tyr Lys Asp
1 5 10 15
Pro Cys Ala Phe Gln Arg Gly Pro Ala Pro Glu Phe Ser Ala Ser Pro
20 25 30
Pro Ala Cys Leu Tyr Met Gly Arg Gln Pro Pro Pro Pro Pro Pro His
35 40 45
Pro Phe Pro Gly Ala Leu Gly Ala Leu Glu Gln Gly Ser Pro Pro Asp
50 55 60
Ile Ser Pro Tyr Glu Val Pro Pro Leu Ala Asp Asp Pro Ala Val Ala
65 70 75 80
His Leu His His His Leu Pro Ala Gln Leu Ala Leu Pro His Pro Pro
85 90 95
Ala Gly Pro Phe Pro Glu Gly Ala Glu Pro Gly Val Leu Glu Glu Pro
100 105 110
Asn Arg Val Gln Leu Pro Phe Pro Trp Met Lys Ser Thr Lys Ala His
115 120 125
Ala Trp Lys Gly Gln Trp Ala Gly Gly Ala Tyr Ala Ala Glu Pro Glu
130 135 140
Glu Asn Lys Arg Thr Arg Thr Ala Tyr Thr Arg Ala Gln Leu Leu Glu
145 150 155 160
Leu Glu Lys Glu Phe Leu Phe Asn Lys Tyr Ile Ser Arg Pro Arg Arg
165 170 175
Val Glu Leu Ala Val Met Leu Asn Leu Thr Glu Arg His Ile Lys Ile
180 185 190
Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys Glu Glu Asp Lys Lys
195 200 205
Arg Gly Gly Gly Thr Ala Val Gly Gly Gly Gly Val Ala Glu Pro Glu
210 215 220
Gln Asp Cys Ala Val Thr Ser Gly Glu Glu Leu Leu Ala Leu Pro Pro
225 230 235 240
Pro Pro Pro Pro Gly Gly Ala Val Pro Pro Ala Ala Pro Val Ala Ala
245 250 255
Arg Glu Gly Arg Leu Pro Pro Gly Leu Ser Ala Ser Pro Gln Pro Ser
260 265 270
Ser Val Ala Pro Arg Arg Pro Gln Glu Pro Arg
275 280
<210> 14
<211> 509
<212> PRT
<213> 人类
<400> 14
Met Asn Leu Leu Asp Pro Phe Met Lys Met Thr Asp Glu Gln Glu Lys
1 5 10 15
Gly Leu Ser Gly Ala Pro Ser Pro Thr Met Ser Glu Asp Ser Ala Gly
20 25 30
Ser Pro Cys Pro Ser Gly Ser Gly Ser Asp Thr Glu Asn Thr Arg Pro
35 40 45
Gln Glu Asn Thr Phe Pro Lys Gly Glu Pro Asp Leu Lys Lys Glu Ser
50 55 60
Glu Glu Asp Lys Phe Pro Val Cys Ile Arg Glu Ala Val Ser Gln Val
65 70 75 80
Leu Lys Gly Tyr Asp Trp Thr Leu Val Pro Met Pro Val Arg Val Asn
85 90 95
Gly Ser Ser Lys Asn Lys Pro His Val Lys Arg Pro Met Asn Ala Phe
100 105 110
Met Val Trp Ala Gln Ala Ala Arg Arg Lys Leu Ala Asp Gln Tyr Pro
115 120 125
His Leu His Asn Ala Glu Leu Ser Lys Thr Leu Gly Lys Leu Trp Arg
130 135 140
Leu Leu Asn Glu Ser Glu Lys Arg Pro Phe Val Glu Glu Ala Glu Arg
145 150 155 160
Leu Arg Val Gln His Lys Lys Asp His Pro Asp Tyr Lys Tyr Gln Pro
165 170 175
Arg Arg Arg Lys Ser Val Lys Asn Gly Gln Ala Glu Ala Glu Glu Ala
180 185 190
Thr Glu Gln Thr His Ile Ser Pro Asn Ala Ile Phe Lys Ala Leu Gln
195 200 205
Ala Asp Ser Pro His Ser Ser Ser Gly Met Ser Glu Val His Ser Pro
210 215 220
Gly Glu His Ser Gly Gln Ser Gln Gly Pro Pro Thr Pro Pro Thr Thr
225 230 235 240
Pro Lys Thr Asp Val Gln Pro Gly Lys Ala Asp Leu Lys Arg Glu Gly
245 250 255
Arg Pro Leu Pro Glu Gly Gly Arg Gln Pro Pro Ile Asp Phe Arg Asp
260 265 270
Val Asp Ile Gly Glu Leu Ser Ser Asp Val Ile Ser Asn Ile Glu Thr
275 280 285
Phe Asp Val Asn Glu Phe Asp Gln Tyr Leu Pro Pro Asn Gly His Pro
290 295 300
Gly Val Pro Ala Thr His Gly Gln Val Thr Tyr Thr Gly Ser Tyr Gly
305 310 315 320
Ile Ser Ser Thr Ala Ala Thr Pro Ala Ser Ala Gly His Val Trp Met
325 330 335
Ser Lys Gln Gln Ala Pro Pro Pro Pro Pro Gln Gln Pro Pro Gln Ala
340 345 350
Pro Pro Ala Pro Gln Ala Pro Pro Gln Pro Gln Ala Ala Pro Pro Gln
355 360 365
Gln Pro Ala Ala Pro Pro Gln Gln Pro Gln Ala His Thr Leu Thr Thr
370 375 380
Leu Ser Ser Glu Pro Gly Gln Ser Gln Arg Thr His Ile Lys Thr Glu
385 390 395 400
Gln Leu Ser Pro Ser His Tyr Ser Glu Gln Gln Gln His Ser Pro Gln
405 410 415
Gln Ile Ala Tyr Ser Pro Phe Asn Leu Pro His Tyr Ser Pro Ser Tyr
420 425 430
Pro Pro Ile Thr Arg Ser Gln Tyr Asp Tyr Thr Asp His Gln Asn Ser
435 440 445
Ser Ser Tyr Tyr Ser His Ala Ala Gly Gln Gly Thr Gly Leu Tyr Ser
450 455 460
Thr Phe Thr Tyr Met Asn Pro Ala Gln Arg Pro Met Tyr Thr Pro Ile
465 470 475 480
Ala Asp Thr Ser Gly Val Pro Ser Ile Pro Gln Thr His Ser Pro Gln
485 490 495
His Trp Glu Gln Pro Val Tyr Thr Gln Leu Thr Arg Pro
500 505
<210> 15
<211> 268
<212> PRT
<213> 人类
<400> 15
Met Pro Arg Ser Phe Leu Val Lys Lys His Phe Asn Ala Ser Lys Lys
1 5 10 15
Pro Asn Tyr Ser Glu Leu Asp Thr His Thr Val Ile Ile Ser Pro Tyr
20 25 30
Leu Tyr Glu Ser Tyr Ser Met Pro Val Ile Pro Gln Pro Glu Ile Leu
35 40 45
Ser Ser Gly Ala Tyr Ser Pro Ile Thr Val Trp Thr Thr Ala Ala Pro
50 55 60
Phe His Ala Gln Leu Pro Asn Gly Leu Ser Pro Leu Ser Gly Tyr Ser
65 70 75 80
Ser Ser Leu Gly Arg Val Ser Pro Pro Pro Pro Ser Asp Thr Ser Ser
85 90 95
Lys Asp His Ser Gly Ser Glu Ser Pro Ile Ser Asp Glu Glu Glu Arg
100 105 110
Leu Gln Ser Lys Leu Ser Asp Pro His Ala Ile Glu Ala Glu Lys Phe
115 120 125
Gln Cys Asn Leu Cys Asn Lys Thr Tyr Ser Thr Phe Ser Gly Leu Ala
130 135 140
Lys His Lys Gln Leu His Cys Asp Ala Gln Ser Arg Lys Ser Phe Ser
145 150 155 160
Cys Lys Tyr Cys Asp Lys Glu Tyr Val Ser Leu Gly Ala Leu Lys Met
165 170 175
His Ile Arg Thr His Thr Leu Pro Cys Val Cys Lys Ile Cys Gly Lys
180 185 190
Ala Phe Ser Arg Pro Trp Leu Leu Gln Gly His Ile Arg Thr His Thr
195 200 205
Gly Glu Lys Pro Phe Ser Cys Pro His Cys Asn Arg Ala Phe Ala Asp
210 215 220
Arg Ser Asn Leu Arg Ala His Leu Gln Thr His Ser Asp Val Lys Lys
225 230 235 240
Tyr Gln Cys Lys Asn Cys Ser Lys Thr Phe Ser Arg Met Ser Leu Leu
245 250 255
His Lys His Glu Glu Ser Gly Cys Cys Val Ala His
260 265
<210> 16
<211> 353
<212> PRT
<213> 人类
<400> 16
Met Ala Ala Glu Leu Ala Met Gly Ala Glu Leu Pro Ser Ser Pro Leu
1 5 10 15
Ala Ile Glu Tyr Val Asn Asp Phe Asp Leu Met Lys Phe Glu Val Lys
20 25 30
Lys Glu Pro Pro Glu Ala Glu Arg Phe Cys His Arg Leu Pro Pro Gly
35 40 45
Ser Leu Ser Ser Thr Pro Leu Ser Thr Pro Cys Ser Ser Val Pro Ser
50 55 60
Ser Pro Ser Phe Cys Ala Pro Ser Pro Gly Thr Gly Gly Gly Gly Gly
65 70 75 80
Ala Gly Gly Gly Gly Gly Ser Ser Gln Ala Gly Gly Ala Pro Gly Pro
85 90 95
Pro Ser Gly Gly Pro Gly Ala Val Gly Gly Thr Ser Gly Lys Pro Ala
100 105 110
Leu Glu Asp Leu Tyr Trp Met Ser Gly Tyr Gln His His Leu Asn Pro
115 120 125
Glu Ala Leu Asn Leu Thr Pro Glu Asp Ala Val Glu Ala Leu Ile Gly
130 135 140
Ser Gly His His Gly Ala His His Gly Ala His His Pro Ala Ala Ala
145 150 155 160
Ala Ala Tyr Glu Ala Phe Arg Gly Pro Gly Phe Ala Gly Gly Gly Gly
165 170 175
Ala Asp Asp Met Gly Ala Gly His His His Gly Ala His His Ala Ala
180 185 190
His His His His Ala Ala His His His His His His His His His His
195 200 205
Gly Gly Ala Gly His Gly Gly Gly Ala Gly His His Val Arg Leu Glu
210 215 220
Glu Arg Phe Ser Asp Asp Gln Leu Val Ser Met Ser Val Arg Glu Leu
225 230 235 240
Asn Arg Gln Leu Arg Gly Phe Ser Lys Glu Glu Val Ile Arg Leu Lys
245 250 255
Gln Lys Arg Arg Thr Leu Lys Asn Arg Gly Tyr Ala Gln Ser Cys Arg
260 265 270
Phe Lys Arg Val Gln Gln Arg His Ile Leu Glu Ser Glu Lys Cys Gln
275 280 285
Leu Gln Ser Gln Val Glu Gln Leu Lys Leu Glu Val Gly Arg Leu Ala
290 295 300
Lys Glu Arg Asp Leu Tyr Lys Glu Lys Tyr Glu Lys Leu Ala Gly Arg
305 310 315 320
Gly Gly Pro Gly Ser Ala Gly Gly Ala Gly Phe Pro Arg Glu Pro Ser
325 330 335
Pro Pro Gln Ala Gly Pro Gly Gly Ala Lys Gly Thr Ala Asp Phe Phe
340 345 350
Leu
<210> 17
<211> 356
<212> PRT
<213> 人类
<400> 17
Met Thr Lys Ser Tyr Ser Glu Ser Gly Leu Met Gly Glu Pro Gln Pro
1 5 10 15
Gln Gly Pro Pro Ser Trp Thr Asp Glu Cys Leu Ser Ser Gln Asp Glu
20 25 30
Glu His Glu Ala Asp Lys Lys Glu Asp Asp Leu Glu Ala Met Asn Ala
35 40 45
Glu Glu Asp Ser Leu Arg Asn Gly Gly Glu Glu Glu Asp Glu Asp Glu
50 55 60
Asp Leu Glu Glu Glu Glu Glu Glu Glu Glu Glu Asp Asp Asp Gln Lys
65 70 75 80
Pro Lys Arg Arg Gly Pro Lys Lys Lys Lys Met Thr Lys Ala Arg Leu
85 90 95
Glu Arg Phe Lys Leu Arg Arg Met Lys Ala Asn Ala Arg Glu Arg Asn
100 105 110
Arg Met His Gly Leu Asn Ala Ala Leu Asp Asn Leu Arg Lys Val Val
115 120 125
Pro Cys Tyr Ser Lys Thr Gln Lys Leu Ser Lys Ile Glu Thr Leu Arg
130 135 140
Leu Ala Lys Asn Tyr Ile Trp Ala Leu Ser Glu Ile Leu Arg Ser Gly
145 150 155 160
Lys Ser Pro Asp Leu Val Ser Phe Val Gln Thr Leu Cys Lys Gly Leu
165 170 175
Ser Gln Pro Thr Thr Asn Leu Val Ala Gly Cys Leu Gln Leu Asn Pro
180 185 190
Arg Thr Phe Leu Pro Glu Gln Asn Gln Asp Met Pro Pro His Leu Pro
195 200 205
Thr Ala Ser Ala Ser Phe Pro Val His Pro Tyr Ser Tyr Gln Ser Pro
210 215 220
Gly Leu Pro Ser Pro Pro Tyr Gly Thr Met Asp Ser Ser His Val Phe
225 230 235 240
His Val Lys Pro Pro Pro His Ala Tyr Ser Ala Ala Leu Glu Pro Phe
245 250 255
Phe Glu Ser Pro Leu Thr Asp Cys Thr Ser Pro Ser Phe Asp Gly Pro
260 265 270
Leu Ser Pro Pro Leu Ser Ile Asn Gly Asn Phe Ser Phe Lys His Glu
275 280 285
Pro Ser Ala Glu Phe Glu Lys Asn Tyr Ala Phe Thr Met His Tyr Pro
290 295 300
Ala Ala Thr Leu Ala Gly Ala Gln Ser His Gly Ser Ile Phe Ser Gly
305 310 315 320
Thr Ala Ala Pro Arg Cys Glu Ile Pro Ile Asp Asn Ile Met Ser Phe
325 330 335
Asp Ser His Ser His His Glu Arg Val Met Ser Ala Gln Leu Asn Ala
340 345 350
Ile Phe His Asp
355
<210> 18
<211> 255
<212> PRT
<213> 人类
<400> 18
Met Asp Val Met Asp Gly Cys Gln Phe Ser Pro Ser Glu Tyr Phe Tyr
1 5 10 15
Asp Gly Ser Cys Ile Pro Ser Pro Glu Gly Glu Phe Gly Asp Glu Phe
20 25 30
Val Pro Arg Val Ala Ala Phe Gly Ala His Lys Ala Glu Leu Gln Gly
35 40 45
Ser Asp Glu Asp Glu His Val Arg Ala Pro Thr Gly His His Gln Ala
50 55 60
Gly His Cys Leu Met Trp Ala Cys Lys Ala Cys Lys Arg Lys Ser Thr
65 70 75 80
Thr Met Asp Arg Arg Lys Ala Ala Thr Met Arg Glu Arg Arg Arg Leu
85 90 95
Lys Lys Val Asn Gln Ala Phe Glu Thr Leu Lys Arg Cys Thr Thr Thr
100 105 110
Asn Pro Asn Gln Arg Leu Pro Lys Val Glu Ile Leu Arg Asn Ala Ile
115 120 125
Arg Tyr Ile Glu Ser Leu Gln Glu Leu Leu Arg Glu Gln Val Glu Asn
130 135 140
Tyr Tyr Ser Leu Pro Gly Gln Ser Cys Ser Glu Pro Thr Ser Pro Thr
145 150 155 160
Ser Asn Cys Ser Asp Gly Met Pro Glu Cys Asn Ser Pro Val Trp Ser
165 170 175
Arg Lys Ser Ser Thr Phe Asp Ser Ile Tyr Cys Pro Asp Val Ser Asn
180 185 190
Val Tyr Ala Thr Asp Lys Asn Ser Leu Ser Ser Leu Asp Cys Leu Ser
195 200 205
Asn Ile Val Asp Arg Ile Thr Ser Ser Glu Gln Pro Gly Leu Pro Leu
210 215 220
Gln Asp Leu Ala Ser Leu Ser Pro Val Ala Ser Thr Asp Ser Gln Pro
225 230 235 240
Ala Thr Pro Gly Ala Ser Ser Ser Arg Leu Ile Tyr His Val Leu
245 250 255
<210> 19
<211> 1276
<212> PRT
<213> 人类
<400> 19
Met Arg Ser Lys Ala Arg Ala Arg Lys Leu Ala Lys Ser Asp Gly Asp
1 5 10 15
Val Val Asn Asn Met Tyr Glu Pro Asn Arg Asp Leu Leu Ala Ser His
20 25 30
Ser Ala Glu Asp Glu Ala Glu Asp Ser Ala Met Ser Pro Ile Pro Val
35 40 45
Gly Ser Pro Pro Pro Phe Pro Thr Ser Glu Asp Phe Thr Pro Lys Glu
50 55 60
Gly Ser Pro Tyr Glu Ala Pro Val Tyr Ile Pro Glu Asp Ile Pro Ile
65 70 75 80
Pro Ala Asp Phe Glu Leu Arg Glu Ser Ser Ile Pro Gly Ala Gly Leu
85 90 95
Gly Val Trp Ala Lys Arg Lys Met Glu Ala Gly Glu Arg Leu Gly Pro
100 105 110
Cys Val Val Val Pro Arg Ala Ala Ala Lys Glu Thr Asp Phe Gly Trp
115 120 125
Glu Gln Ile Leu Thr Asp Val Glu Val Ser Pro Gln Glu Gly Cys Ile
130 135 140
Thr Lys Ile Ser Glu Asp Leu Gly Ser Glu Lys Phe Cys Val Asp Ala
145 150 155 160
Asn Gln Ala Gly Ala Gly Ser Trp Leu Lys Tyr Ile Arg Val Ala Cys
165 170 175
Ser Cys Asp Asp Gln Asn Leu Thr Met Cys Gln Ile Ser Glu Gln Val
180 185 190
Ile Tyr Tyr Lys Val Ile Lys Asp Ile Glu Pro Gly Glu Glu Leu Leu
195 200 205
Val His Val Lys Glu Gly Val Tyr Pro Leu Gly Thr Val Pro Pro Gly
210 215 220
Leu Asp Glu Glu Pro Thr Phe Arg Cys Asp Glu Cys Asp Glu Leu Phe
225 230 235 240
Gln Ser Lys Leu Asp Leu Arg Arg His Lys Lys Tyr Thr Cys Gly Ser
245 250 255
Val Gly Ala Ala Leu Tyr Glu Gly Leu Ala Glu Glu Leu Lys Pro Glu
260 265 270
Gly Leu Gly Gly Gly Ser Gly Gln Ala His Glu Cys Lys Asp Cys Glu
275 280 285
Arg Met Phe Pro Asn Lys Tyr Ser Leu Glu Gln His Met Val Ile His
290 295 300
Thr Glu Glu Arg Glu Tyr Lys Cys Asp Gln Cys Pro Lys Ala Phe Asn
305 310 315 320
Trp Lys Ser Asn Phe Ile Arg His Gln Met Ser His Asp Ser Gly Lys
325 330 335
Arg Phe Glu Cys Glu Asn Cys Val Lys Val Phe Thr Asp Pro Ser Asn
340 345 350
Leu Gln Arg His Ile Arg Ser Gln His Val Gly Ala Arg Ala His Ala
355 360 365
Cys Pro Asp Cys Gly Lys Thr Phe Ala Thr Ser Ser Gly Leu Lys Gln
370 375 380
His Lys His Ile His Ser Thr Val Lys Pro Phe Ile Cys Glu Val Cys
385 390 395 400
His Lys Ser Tyr Thr Gln Phe Ser Asn Leu Cys Arg His Lys Arg Met
405 410 415
His Ala Asp Cys Arg Thr Gln Ile Lys Cys Lys Asp Cys Gly Gln Met
420 425 430
Phe Ser Thr Thr Ser Ser Leu Asn Lys His Arg Arg Phe Cys Glu Gly
435 440 445
Lys Asn His Tyr Thr Pro Gly Gly Ile Phe Ala Pro Gly Leu Pro Leu
450 455 460
Thr Pro Ser Pro Met Met Asp Lys Ala Lys Pro Ser Pro Ser Leu Asn
465 470 475 480
His Ala Ser Leu Gly Phe Asn Glu Tyr Phe Pro Tyr Arg Pro His Pro
485 490 495
Gly Ser Leu Pro Phe Ser Thr Ala Pro Pro Thr Phe Pro Ala Leu Thr
500 505 510
Pro Gly Phe Pro Gly Ile Phe Pro Pro Ser Leu Tyr Pro Arg Pro Pro
515 520 525
Leu Leu Pro Pro Thr Ser Leu Leu Lys Ser Pro Leu Asn His Thr Gln
530 535 540
Asp Ala Lys Leu Pro Ser Pro Leu Gly Asn Pro Ala Leu Pro Leu Val
545 550 555 560
Ser Ala Val Ser Asn Ser Ser Gln Gly Thr Thr Ala Ala Ala Gly Pro
565 570 575
Glu Glu Lys Phe Glu Ser Arg Leu Glu Asp Ser Cys Val Glu Lys Leu
580 585 590
Lys Thr Arg Ser Ser Asp Met Ser Asp Gly Ser Asp Phe Glu Asp Val
595 600 605
Asn Thr Thr Thr Gly Thr Asp Leu Asp Thr Thr Thr Gly Thr Gly Ser
610 615 620
Asp Leu Asp Ser Asp Val Asp Ser Asp Pro Asp Lys Asp Lys Gly Lys
625 630 635 640
Gly Lys Ser Ala Glu Gly Gln Pro Lys Phe Gly Gly Gly Leu Ala Pro
645 650 655
Pro Gly Ala Pro Asn Ser Val Ala Glu Val Pro Val Phe Tyr Ser Gln
660 665 670
His Ser Phe Phe Pro Pro Pro Asp Glu Gln Leu Leu Thr Ala Thr Gly
675 680 685
Ala Ala Gly Asp Ser Ile Lys Ala Ile Ala Ser Ile Ala Glu Lys Tyr
690 695 700
Phe Gly Pro Gly Phe Met Gly Met Gln Glu Lys Lys Leu Gly Ser Leu
705 710 715 720
Pro Tyr His Ser Ala Phe Pro Phe Gln Phe Leu Pro Asn Phe Pro His
725 730 735
Ser Leu Tyr Pro Phe Thr Asp Arg Ala Leu Ala His Asn Leu Leu Val
740 745 750
Lys Ala Glu Pro Lys Ser Pro Arg Asp Ala Leu Lys Val Gly Gly Pro
755 760 765
Ser Ala Glu Cys Pro Phe Asp Leu Thr Thr Lys Pro Lys Asp Val Lys
770 775 780
Pro Ile Leu Pro Met Pro Lys Gly Pro Ser Ala Pro Ala Ser Gly Glu
785 790 795 800
Glu Gln Pro Leu Asp Leu Ser Ile Gly Ser Arg Ala Arg Ala Ser Gln
805 810 815
Asn Gly Gly Gly Arg Glu Pro Arg Lys Asn His Val Tyr Gly Glu Arg
820 825 830
Lys Leu Gly Ala Gly Glu Gly Leu Pro Gln Val Cys Pro Ala Arg Met
835 840 845
Pro Gln Gln Pro Pro Leu His Tyr Ala Lys Pro Ser Pro Phe Phe Met
850 855 860
Asp Pro Ile Tyr Arg Val Glu Lys Arg Lys Val Thr Asp Pro Val Gly
865 870 875 880
Ala Leu Lys Glu Lys Tyr Leu Arg Pro Ser Pro Leu Leu Phe His Pro
885 890 895
Gln Met Ser Ala Ile Glu Thr Met Thr Glu Lys Leu Glu Ser Phe Ala
900 905 910
Ala Met Lys Ala Asp Ser Gly Ser Ser Leu Gln Pro Leu Pro His His
915 920 925
Pro Phe Asn Phe Arg Ser Pro Pro Pro Thr Leu Ser Asp Pro Ile Leu
930 935 940
Arg Lys Gly Lys Glu Arg Tyr Thr Cys Arg Tyr Cys Gly Lys Ile Phe
945 950 955 960
Pro Arg Ser Ala Asn Leu Thr Arg His Leu Arg Thr His Thr Gly Glu
965 970 975
Gln Pro Tyr Arg Cys Lys Tyr Cys Asp Arg Ser Phe Ser Ile Ser Ser
980 985 990
Asn Leu Gln Arg His Val Arg Asn Ile His Asn Lys Glu Lys Pro Phe
995 1000 1005
Lys Cys His Leu Cys Asn Arg Cys Phe Gly Gln Gln Thr Asn Leu
1010 1015 1020
Asp Arg His Leu Lys Lys His Glu His Glu Asn Ala Pro Val Ser
1025 1030 1035
Gln His Pro Gly Val Leu Thr Asn His Leu Gly Thr Ser Ala Ser
1040 1045 1050
Ser Pro Thr Ser Glu Ser Asp Asn His Ala Leu Leu Asp Glu Lys
1055 1060 1065
Glu Asp Ser Tyr Phe Ser Glu Ile Arg Asn Phe Ile Ala Asn Ser
1070 1075 1080
Glu Met Asn Gln Ala Ser Thr Arg Thr Glu Lys Arg Ala Asp Met
1085 1090 1095
Gln Ile Val Asp Gly Ser Ala Gln Cys Pro Gly Leu Ala Ser Glu
1100 1105 1110
Lys Gln Glu Asp Val Glu Glu Glu Asp Asp Asp Asp Leu Glu Glu
1115 1120 1125
Asp Asp Glu Asp Ser Leu Ala Gly Lys Ser Gln Asp Asp Thr Val
1130 1135 1140
Ser Pro Ala Pro Glu Pro Gln Ala Ala Tyr Glu Asp Glu Glu Asp
1145 1150 1155
Glu Glu Pro Ala Ala Ser Leu Ala Val Gly Phe Asp His Thr Arg
1160 1165 1170
Arg Cys Ala Glu Asp His Glu Gly Gly Leu Leu Ala Leu Glu Pro
1175 1180 1185
Met Pro Thr Phe Gly Lys Gly Leu Asp Leu Arg Arg Ala Ala Glu
1190 1195 1200
Glu Ala Phe Glu Val Lys Asp Val Leu Asn Ser Thr Leu Asp Ser
1205 1210 1215
Glu Ala Leu Lys His Thr Leu Cys Arg Gln Ala Lys Asn Gln Ala
1220 1225 1230
Tyr Ala Met Met Leu Ser Leu Ser Glu Asp Thr Pro Leu His Thr
1235 1240 1245
Pro Ser Gln Gly Ser Leu Asp Ala Trp Leu Lys Val Thr Gly Ala
1250 1255 1260
Thr Ser Glu Ser Gly Ala Phe His Pro Ile Asn His Leu
1265 1270 1275
<210> 20
<211> 436
<212> PRT
<213> 人类
<400> 20
Met Gln Asn Ser His Ser Gly Val Asn Gln Leu Gly Gly Val Phe Val
1 5 10 15
Asn Gly Arg Pro Leu Pro Asp Ser Thr Arg Gln Lys Ile Val Glu Leu
20 25 30
Ala His Ser Gly Ala Arg Pro Cys Asp Ile Ser Arg Ile Leu Gln Thr
35 40 45
His Ala Asp Ala Lys Val Gln Val Leu Asp Asn Gln Asn Val Ser Asn
50 55 60
Gly Cys Val Ser Lys Ile Leu Gly Arg Tyr Tyr Glu Thr Gly Ser Ile
65 70 75 80
Arg Pro Arg Ala Ile Gly Gly Ser Lys Pro Arg Val Ala Thr Pro Glu
85 90 95
Val Val Ser Lys Ile Ala Gln Tyr Lys Arg Glu Cys Pro Ser Ile Phe
100 105 110
Ala Trp Glu Ile Arg Asp Arg Leu Leu Ser Glu Gly Val Cys Thr Asn
115 120 125
Asp Asn Ile Pro Ser Val Ser Ser Ile Asn Arg Val Leu Arg Asn Leu
130 135 140
Ala Ser Glu Lys Gln Gln Met Gly Ala Asp Gly Met Tyr Asp Lys Leu
145 150 155 160
Arg Met Leu Asn Gly Gln Thr Gly Ser Trp Gly Thr Arg Pro Gly Trp
165 170 175
Tyr Pro Gly Thr Ser Val Pro Gly Gln Pro Thr Gln Asp Gly Cys Gln
180 185 190
Gln Gln Glu Gly Gly Gly Glu Asn Thr Asn Ser Ile Ser Ser Asn Gly
195 200 205
Glu Asp Ser Asp Glu Ala Gln Met Arg Leu Gln Leu Lys Arg Lys Leu
210 215 220
Gln Arg Asn Arg Thr Ser Phe Thr Gln Glu Gln Ile Glu Ala Leu Glu
225 230 235 240
Lys Glu Phe Glu Arg Thr His Tyr Pro Asp Val Phe Ala Arg Glu Arg
245 250 255
Leu Ala Ala Lys Ile Asp Leu Pro Glu Ala Arg Ile Gln Val Trp Phe
260 265 270
Ser Asn Arg Arg Ala Lys Trp Arg Arg Glu Glu Lys Leu Arg Asn Gln
275 280 285
Arg Arg Gln Ala Ser Asn Thr Pro Ser His Ile Pro Ile Ser Ser Ser
290 295 300
Phe Ser Thr Ser Val Tyr Gln Pro Ile Pro Gln Pro Thr Thr Pro Val
305 310 315 320
Ser Ser Phe Thr Ser Gly Ser Met Leu Gly Arg Thr Asp Thr Ala Leu
325 330 335
Thr Asn Thr Tyr Ser Ala Leu Pro Pro Met Pro Ser Phe Thr Met Ala
340 345 350
Asn Asn Leu Pro Met Gln Pro Pro Val Pro Ser Gln Thr Ser Ser Tyr
355 360 365
Ser Cys Met Leu Pro Thr Ser Pro Ser Val Asn Gly Arg Ser Tyr Asp
370 375 380
Thr Tyr Thr Pro Pro His Met Gln Thr His Met Asn Ser Gln Pro Met
385 390 395 400
Gly Thr Ser Gly Thr Thr Ser Thr Gly Leu Ile Ser Pro Gly Val Ser
405 410 415
Val Pro Val Gln Val Pro Gly Ser Glu Pro Asp Met Ser Gln Tyr Trp
420 425 430
Pro Arg Leu Gln
435
<210> 21
<211> 631
<212> PRT
<213> 人类
<400> 21
Met Val Ser Lys Leu Ser Gln Leu Gln Thr Glu Leu Leu Ala Ala Leu
1 5 10 15
Leu Glu Ser Gly Leu Ser Lys Glu Ala Leu Ile Gln Ala Leu Gly Glu
20 25 30
Pro Gly Pro Tyr Leu Leu Ala Gly Glu Gly Pro Leu Asp Lys Gly Glu
35 40 45
Ser Cys Gly Gly Gly Arg Gly Glu Leu Ala Glu Leu Pro Asn Gly Leu
50 55 60
Gly Glu Thr Arg Gly Ser Glu Asp Glu Thr Asp Asp Asp Gly Glu Asp
65 70 75 80
Phe Thr Pro Pro Ile Leu Lys Glu Leu Glu Asn Leu Ser Pro Glu Glu
85 90 95
Ala Ala His Gln Lys Ala Val Val Glu Thr Leu Leu Gln Glu Asp Pro
100 105 110
Trp Arg Val Ala Lys Met Val Lys Ser Tyr Leu Gln Gln His Asn Ile
115 120 125
Pro Gln Arg Glu Val Val Asp Thr Thr Gly Leu Asn Gln Ser His Leu
130 135 140
Ser Gln His Leu Asn Lys Gly Thr Pro Met Lys Thr Gln Lys Arg Ala
145 150 155 160
Ala Leu Tyr Thr Trp Tyr Val Arg Lys Gln Arg Glu Val Ala Gln Gln
165 170 175
Phe Thr His Ala Gly Gln Gly Gly Leu Ile Glu Glu Pro Thr Gly Asp
180 185 190
Glu Leu Pro Thr Lys Lys Gly Arg Arg Asn Arg Phe Lys Trp Gly Pro
195 200 205
Ala Ser Gln Gln Ile Leu Phe Gln Ala Tyr Glu Arg Gln Lys Asn Pro
210 215 220
Ser Lys Glu Glu Arg Glu Thr Leu Val Glu Glu Cys Asn Arg Ala Glu
225 230 235 240
Cys Ile Gln Arg Gly Val Ser Pro Ser Gln Ala Gln Gly Leu Gly Ser
245 250 255
Asn Leu Val Thr Glu Val Arg Val Tyr Asn Trp Phe Ala Asn Arg Arg
260 265 270
Lys Glu Glu Ala Phe Arg His Lys Leu Ala Met Asp Thr Tyr Ser Gly
275 280 285
Pro Pro Pro Gly Pro Gly Pro Gly Pro Ala Leu Pro Ala His Ser Ser
290 295 300
Pro Gly Leu Pro Pro Pro Ala Leu Ser Pro Ser Lys Val His Gly Val
305 310 315 320
Arg Tyr Gly Gln Pro Ala Thr Ser Glu Thr Ala Glu Val Pro Ser Ser
325 330 335
Ser Gly Gly Pro Leu Val Thr Val Ser Thr Pro Leu His Gln Val Ser
340 345 350
Pro Thr Gly Leu Glu Pro Ser His Ser Leu Leu Ser Thr Glu Ala Lys
355 360 365
Leu Val Ser Ala Ala Gly Gly Pro Leu Pro Pro Val Ser Thr Leu Thr
370 375 380
Ala Leu His Ser Leu Glu Gln Thr Ser Pro Gly Leu Asn Gln Gln Pro
385 390 395 400
Gln Asn Leu Ile Met Ala Ser Leu Pro Gly Val Met Thr Ile Gly Pro
405 410 415
Gly Glu Pro Ala Ser Leu Gly Pro Thr Phe Thr Asn Thr Gly Ala Ser
420 425 430
Thr Leu Val Ile Gly Leu Ala Ser Thr Gln Ala Gln Ser Val Pro Val
435 440 445
Ile Asn Ser Met Gly Ser Ser Leu Thr Thr Leu Gln Pro Val Gln Phe
450 455 460
Ser Gln Pro Leu His Pro Ser Tyr Gln Gln Pro Leu Met Pro Pro Val
465 470 475 480
Gln Ser His Val Thr Gln Ser Pro Phe Met Ala Thr Met Ala Gln Leu
485 490 495
Gln Ser Pro His Ala Leu Tyr Ser His Lys Pro Glu Val Ala Gln Tyr
500 505 510
Thr His Thr Gly Leu Leu Pro Gln Thr Met Leu Ile Thr Asp Thr Thr
515 520 525
Asn Leu Ser Ala Leu Ala Ser Leu Thr Pro Thr Lys Gln Val Phe Thr
530 535 540
Ser Asp Thr Glu Ala Ser Ser Glu Ser Gly Leu His Thr Pro Ala Ser
545 550 555 560
Gln Ala Thr Thr Leu His Val Pro Ser Gln Asp Pro Ala Gly Ile Gln
565 570 575
His Leu Gln Pro Ala His Arg Leu Ser Ala Ser Pro Thr Val Ser Ser
580 585 590
Ser Ser Leu Val Leu Tyr Gln Ser Ser Asp Ser Ser Asn Gly Gln Ser
595 600 605
His Leu Leu Pro Ser Asn His Ser Val Ile Glu Thr Phe Ile Ser Thr
610 615 620
Gln Met Ala Ser Ser Ser Gln
625 630
<210> 22
<211> 350
<212> PRT
<213> 人类
<400> 22
Met Leu Gly Ser Val Lys Met Glu Ala His Asp Leu Ala Glu Trp Ser
1 5 10 15
Tyr Tyr Pro Glu Ala Gly Glu Val Tyr Ser Pro Val Thr Pro Val Pro
20 25 30
Thr Met Ala Pro Leu Asn Ser Tyr Met Thr Leu Asn Pro Leu Ser Ser
35 40 45
Pro Tyr Pro Pro Gly Gly Leu Pro Ala Ser Pro Leu Pro Ser Gly Pro
50 55 60
Leu Ala Pro Pro Ala Pro Ala Ala Pro Leu Gly Pro Thr Phe Pro Gly
65 70 75 80
Leu Gly Val Ser Gly Gly Ser Ser Ser Ser Gly Tyr Gly Ala Pro Gly
85 90 95
Pro Gly Leu Val His Gly Lys Glu Met Pro Lys Gly Tyr Arg Arg Pro
100 105 110
Leu Ala His Ala Lys Pro Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met
115 120 125
Ala Ile Gln Gln Ala Pro Gly Lys Met Leu Thr Leu Ser Glu Ile Tyr
130 135 140
Gln Trp Ile Met Asp Leu Phe Pro Tyr Tyr Arg Glu Asn Gln Gln Arg
145 150 155 160
Trp Gln Asn Ser Ile Arg His Ser Leu Ser Phe Asn Asp Cys Phe Val
165 170 175
Lys Val Ala Arg Ser Pro Asp Lys Pro Gly Lys Gly Ser Tyr Trp Ala
180 185 190
Leu His Pro Ser Ser Gly Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg
195 200 205
Arg Gln Lys Arg Phe Lys Leu Glu Glu Lys Val Lys Lys Gly Gly Ser
210 215 220
Gly Ala Ala Thr Thr Thr Arg Asn Gly Thr Gly Ser Ala Ala Ser Thr
225 230 235 240
Thr Thr Pro Ala Ala Thr Val Thr Ser Pro Pro Gln Pro Pro Pro Pro
245 250 255
Ala Pro Glu Pro Glu Ala Gln Gly Gly Glu Asp Val Gly Ala Leu Asp
260 265 270
Cys Gly Ser Pro Ala Ser Ser Thr Pro Tyr Phe Thr Gly Leu Glu Leu
275 280 285
Pro Gly Glu Leu Lys Leu Asp Ala Pro Tyr Asn Phe Asn His Pro Phe
290 295 300
Ser Ile Asn Asn Leu Met Ser Glu Gln Thr Pro Ala Pro Pro Lys Leu
305 310 315 320
Asp Val Gly Phe Gly Gly Tyr Gly Ala Glu Gly Gly Glu Pro Gly Val
325 330 335
Tyr Tyr Gln Gly Leu Tyr Ser Arg Ser Leu Leu Asn Ala Ser
340 345 350
<210> 23
<211> 472
<212> PRT
<213> 人类
<400> 23
Met Leu Gly Thr Val Lys Met Glu Gly His Glu Thr Ser Asp Trp Asn
1 5 10 15
Ser Tyr Tyr Ala Asp Thr Gln Glu Ala Tyr Ser Ser Val Pro Val Ser
20 25 30
Asn Met Asn Ser Gly Leu Gly Ser Met Asn Ser Met Asn Thr Tyr Met
35 40 45
Thr Met Asn Thr Met Thr Thr Ser Gly Asn Met Thr Pro Ala Ser Phe
50 55 60
Asn Met Ser Tyr Ala Asn Pro Gly Leu Gly Ala Gly Leu Ser Pro Gly
65 70 75 80
Ala Val Ala Gly Met Pro Gly Gly Ser Ala Gly Ala Met Asn Ser Met
85 90 95
Thr Ala Ala Gly Val Thr Ala Met Gly Thr Ala Leu Ser Pro Ser Gly
100 105 110
Met Gly Ala Met Gly Ala Gln Gln Ala Ala Ser Met Asn Gly Leu Gly
115 120 125
Pro Tyr Ala Ala Ala Met Asn Pro Cys Met Ser Pro Met Ala Tyr Ala
130 135 140
Pro Ser Asn Leu Gly Arg Ser Arg Ala Gly Gly Gly Gly Asp Ala Lys
145 150 155 160
Thr Phe Lys Arg Ser Tyr Pro His Ala Lys Pro Pro Tyr Ser Tyr Ile
165 170 175
Ser Leu Ile Thr Met Ala Ile Gln Gln Ala Pro Ser Lys Met Leu Thr
180 185 190
Leu Ser Glu Ile Tyr Gln Trp Ile Met Asp Leu Phe Pro Tyr Tyr Arg
195 200 205
Gln Asn Gln Gln Arg Trp Gln Asn Ser Ile Arg His Ser Leu Ser Phe
210 215 220
Asn Asp Cys Phe Val Lys Val Ala Arg Ser Pro Asp Lys Pro Gly Lys
225 230 235 240
Gly Ser Tyr Trp Thr Leu His Pro Asp Ser Gly Asn Met Phe Glu Asn
245 250 255
Gly Cys Tyr Leu Arg Arg Gln Lys Arg Phe Lys Cys Glu Lys Gln Pro
260 265 270
Gly Ala Gly Gly Gly Gly Gly Ser Gly Ser Gly Gly Ser Gly Ala Lys
275 280 285
Gly Gly Pro Glu Ser Arg Lys Asp Pro Ser Gly Ala Ser Asn Pro Ser
290 295 300
Ala Asp Ser Pro Leu His Arg Gly Val His Gly Lys Thr Gly Gln Leu
305 310 315 320
Glu Gly Ala Pro Ala Pro Gly Pro Ala Ala Ser Pro Gln Thr Leu Asp
325 330 335
His Ser Gly Ala Thr Ala Thr Gly Gly Ala Ser Glu Leu Lys Thr Pro
340 345 350
Ala Ser Ser Thr Ala Pro Pro Ile Ser Ser Gly Pro Gly Ala Leu Ala
355 360 365
Ser Val Pro Ala Ser His Pro Ala His Gly Leu Ala Pro His Glu Ser
370 375 380
Gln Leu His Leu Lys Gly Asp Pro His Tyr Ser Phe Asn His Pro Phe
385 390 395 400
Ser Ile Asn Asn Leu Met Ser Ser Ser Glu Gln Gln His Lys Leu Asp
405 410 415
Phe Lys Ala Tyr Glu Gln Ala Leu Gln Tyr Ser Pro Tyr Gly Ser Thr
420 425 430
Leu Pro Ala Ser Leu Pro Leu Gly Ser Ala Ser Val Thr Thr Arg Ser
435 440 445
Pro Ile Glu Pro Ser Ala Leu Glu Pro Ala Tyr Tyr Gln Gly Val Tyr
450 455 460
Ser Arg Pro Val Leu Asn Thr Ser
465 470
<210> 24
<211> 463
<212> PRT
<213> 人类
<400> 24
Met His Ser Ala Ser Ser Met Leu Gly Ala Val Lys Met Glu Gly His
1 5 10 15
Glu Pro Ser Asp Trp Ser Ser Tyr Tyr Ala Glu Pro Glu Gly Tyr Ser
20 25 30
Ser Val Ser Asn Met Asn Ala Gly Leu Gly Met Asn Gly Met Asn Thr
35 40 45
Tyr Met Ser Met Ser Ala Ala Ala Met Gly Ser Gly Ser Gly Asn Met
50 55 60
Ser Ala Gly Ser Met Asn Met Ser Ser Tyr Val Gly Ala Gly Met Ser
65 70 75 80
Pro Ser Leu Ala Gly Met Ser Pro Gly Ala Gly Ala Met Ala Gly Met
85 90 95
Gly Gly Ser Ala Gly Ala Ala Gly Val Ala Gly Met Gly Pro His Leu
100 105 110
Ser Pro Ser Leu Ser Pro Leu Gly Gly Gln Ala Ala Gly Ala Met Gly
115 120 125
Gly Leu Ala Pro Tyr Ala Asn Met Asn Ser Met Ser Pro Met Tyr Gly
130 135 140
Gln Ala Gly Leu Ser Arg Ala Arg Asp Pro Lys Thr Tyr Arg Arg Ser
145 150 155 160
Tyr Thr His Ala Lys Pro Pro Tyr Ser Tyr Ile Ser Leu Ile Thr Met
165 170 175
Ala Ile Gln Gln Ser Pro Asn Lys Met Leu Thr Leu Ser Glu Ile Tyr
180 185 190
Gln Trp Ile Met Asp Leu Phe Pro Phe Tyr Arg Gln Asn Gln Gln Arg
195 200 205
Trp Gln Asn Ser Ile Arg His Ser Leu Ser Phe Asn Asp Cys Phe Leu
210 215 220
Lys Val Pro Arg Ser Pro Asp Lys Pro Gly Lys Gly Ser Phe Trp Thr
225 230 235 240
Leu His Pro Asp Ser Gly Asn Met Phe Glu Asn Gly Cys Tyr Leu Arg
245 250 255
Arg Gln Lys Arg Phe Lys Cys Glu Lys Gln Leu Ala Leu Lys Glu Ala
260 265 270
Ala Gly Ala Ala Gly Ser Gly Lys Lys Ala Ala Ala Gly Ala Gln Ala
275 280 285
Ser Gln Ala Gln Leu Gly Glu Ala Ala Gly Pro Ala Ser Glu Thr Pro
290 295 300
Ala Gly Thr Glu Ser Pro His Ser Ser Ala Ser Pro Cys Gln Glu His
305 310 315 320
Lys Arg Gly Gly Leu Gly Glu Leu Lys Gly Thr Pro Ala Ala Ala Leu
325 330 335
Ser Pro Pro Glu Pro Ala Pro Ser Pro Gly Gln Gln Gln Gln Ala Ala
340 345 350
Ala His Leu Leu Gly Pro Pro His His Pro Gly Leu Pro Pro Glu Ala
355 360 365
His Leu Lys Pro Glu His His Tyr Ala Phe Asn His Pro Phe Ser Ile
370 375 380
Asn Asn Leu Met Ser Ser Glu Gln Gln His His His Ser His His His
385 390 395 400
His Gln Pro His Lys Met Asp Leu Lys Ala Tyr Glu Gln Val Met His
405 410 415
Tyr Pro Gly Tyr Gly Ser Pro Met Pro Gly Ser Leu Ala Met Gly Pro
420 425 430
Val Thr Asn Lys Thr Gly Leu Asp Ala Ser Pro Leu Ala Ala Asp Thr
435 440 445
Ser Tyr Tyr Gln Gly Val Tyr Ser Arg Pro Ile Met Asn Ser Ser
450 455 460
<210> 25
<211> 344
<212> PRT
<213> 人类
<400> 25
Met Ser Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala Ala
1 5 10 15
Phe Gly Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro Pro
20 25 30
Ala Ala Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser Ile
35 40 45
Asp Ile Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe Leu
50 55 60
Ala Asp Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala Ala
65 70 75 80
Val Gly Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro Gly
85 90 95
Ala Pro Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His Gly
100 105 110
Pro Pro Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly Arg
115 120 125
Leu Glu Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro Leu
130 135 140
Val Ile Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu Ala
145 150 155 160
Leu Ala Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro Ser
165 170 175
His Pro His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His Leu
180 185 190
Gln Phe Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln Pro
195 200 205
Gly His Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro Ala
210 215 220
Pro Ala Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu Lys
225 230 235 240
Gly Leu Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser Gly
245 250 255
Ala Gly Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr Arg
260 265 270
Val Arg Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp Lys
275 280 285
Ala Lys Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu Thr
290 295 300
Ser Asp Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg Glu
305 310 315 320
Leu Asp Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser Leu
325 330 335
Val Lys Ala Met Gly Asn Cys Ala
340
<210> 26
<211> 271
<212> PRT
<213> 人类
<400> 26
Met Leu Gln Ala Cys Lys Met Glu Gly Phe Pro Leu Val Pro Pro Gln
1 5 10 15
Pro Ser Glu Asp Leu Val Pro Tyr Asp Thr Asp Leu Tyr Gln Arg Gln
20 25 30
Thr His Glu Tyr Tyr Pro Tyr Leu Ser Ser Asp Gly Glu Ser His Ser
35 40 45
Asp His Tyr Trp Asp Phe His Pro His His Val His Ser Glu Phe Glu
50 55 60
Ser Phe Ala Glu Asn Asn Phe Thr Glu Leu Gln Ser Val Gln Pro Pro
65 70 75 80
Gln Leu Gln Gln Leu Tyr Arg His Met Glu Leu Glu Gln Met His Val
85 90 95
Leu Asp Thr Pro Met Val Pro Pro His Pro Ser Leu Gly His Gln Val
100 105 110
Ser Tyr Leu Pro Arg Met Cys Leu Gln Tyr Pro Ser Leu Ser Pro Ala
115 120 125
Gln Pro Ser Ser Asp Glu Glu Glu Gly Glu Arg Gln Ser Pro Pro Leu
130 135 140
Glu Val Ser Asp Gly Glu Ala Asp Gly Leu Glu Pro Gly Pro Gly Leu
145 150 155 160
Leu Pro Gly Glu Thr Gly Ser Lys Lys Lys Ile Arg Leu Tyr Gln Phe
165 170 175
Leu Leu Asp Leu Leu Arg Ser Gly Asp Met Lys Asp Ser Ile Trp Trp
180 185 190
Val Asp Lys Asp Lys Gly Thr Phe Gln Phe Ser Ser Lys His Lys Glu
195 200 205
Ala Leu Ala His Arg Trp Gly Ile Gln Lys Gly Asn Arg Lys Lys Met
210 215 220
Thr Tyr Gln Lys Met Ala Arg Ala Leu Arg Asn Tyr Gly Lys Thr Gly
225 230 235 240
Glu Val Lys Lys Val Lys Lys Lys Leu Thr Tyr Gln Phe Ser Gly Glu
245 250 255
Val Leu Gly Arg Gly Gly Leu Ala Glu Arg Arg His Pro Pro His
260 265 270
<210> 27
<211> 443
<212> PRT
<213> 人类
<400> 27
Met Ala Thr Ala Ala Ser Asn His Tyr Ser Leu Leu Thr Ser Ser Ala
1 5 10 15
Ser Ile Val His Ala Glu Pro Pro Gly Gly Met Gln Gln Gly Ala Gly
20 25 30
Gly Tyr Arg Glu Ala Gln Ser Leu Val Gln Gly Asp Tyr Gly Ala Leu
35 40 45
Gln Ser Asn Gly His Pro Leu Ser His Ala His Gln Trp Ile Thr Ala
50 55 60
Leu Ser His Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
65 70 75 80
Gly Gly Gly Gly Gly Gly Gly Gly Asp Gly Ser Pro Trp Ser Thr Ser
85 90 95
Pro Leu Gly Gln Pro Asp Ile Lys Pro Ser Val Val Val Gln Gln Gly
100 105 110
Gly Arg Gly Asp Glu Leu His Gly Pro Gly Ala Leu Gln Gln Gln His
115 120 125
Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
130 135 140
Gln Gln Gln Gln Gln Arg Pro Pro His Leu Val His His Ala Ala Asn
145 150 155 160
His His Pro Gly Pro Gly Ala Trp Arg Ser Ala Ala Ala Ala Ala His
165 170 175
Leu Pro Pro Ser Met Gly Ala Ser Asn Gly Gly Leu Leu Tyr Ser Gln
180 185 190
Pro Ser Phe Thr Val Asn Gly Met Leu Gly Ala Gly Gly Gln Pro Ala
195 200 205
Gly Leu His His His Gly Leu Arg Asp Ala His Asp Glu Pro His His
210 215 220
Ala Asp His His Pro His Pro His Ser His Pro His Gln Gln Pro Pro
225 230 235 240
Pro Pro Pro Pro Pro Gln Gly Pro Pro Gly His Pro Gly Ala His His
245 250 255
Asp Pro His Ser Asp Glu Asp Thr Pro Thr Ser Asp Asp Leu Glu Gln
260 265 270
Phe Ala Lys Gln Phe Lys Gln Arg Arg Ile Lys Leu Gly Phe Thr Gln
275 280 285
Ala Asp Val Gly Leu Ala Leu Gly Thr Leu Tyr Gly Asn Val Phe Ser
290 295 300
Gln Thr Thr Ile Cys Arg Phe Glu Ala Leu Gln Leu Ser Phe Lys Asn
305 310 315 320
Met Cys Lys Leu Lys Pro Leu Leu Asn Lys Trp Leu Glu Glu Ala Asp
325 330 335
Ser Ser Ser Gly Ser Pro Thr Ser Ile Asp Lys Ile Ala Ala Gln Gly
340 345 350
Arg Lys Arg Lys Lys Arg Thr Ser Ile Glu Val Ser Val Lys Gly Ala
355 360 365
Leu Glu Ser His Phe Leu Lys Cys Pro Lys Pro Ser Ala Gln Glu Ile
370 375 380
Thr Ser Leu Ala Asp Ser Leu Gln Leu Glu Lys Glu Val Val Arg Val
385 390 395 400
Trp Phe Cys Asn Arg Arg Gln Lys Glu Lys Arg Met Thr Pro Pro Gly
405 410 415
Gly Thr Leu Pro Gly Ala Glu Asp Val Tyr Gly Gly Ser Arg Asp Thr
420 425 430
Pro Pro His His Gly Val Gln Thr Pro Val Gln
435 440
<210> 28
<211> 489
<212> PRT
<213> 人类
<400> 28
Met Leu Asp Met Gly Asp Arg Lys Glu Val Lys Met Ile Pro Lys Ser
1 5 10 15
Ser Phe Ser Ile Asn Ser Leu Val Pro Glu Ala Val Gln Asn Asp Asn
20 25 30
His His Ala Ser His Gly His His Asn Ser His His Pro Gln His His
35 40 45
His His His His His His His His His Pro Pro Pro Pro Ala Pro Gln
50 55 60
Pro Pro Pro Pro Pro Gln Gln Gln Gln Pro Pro Pro Pro Pro Pro Pro
65 70 75 80
Ala Pro Gln Pro Pro Gln Thr Arg Gly Ala Pro Ala Ala Asp Asp Asp
85 90 95
Lys Gly Pro Gln Gln Leu Leu Leu Pro Pro Pro Pro Pro Pro Pro Pro
100 105 110
Ala Ala Ala Leu Asp Gly Ala Lys Ala Asp Gly Leu Gly Gly Lys Gly
115 120 125
Glu Pro Gly Gly Gly Pro Gly Glu Leu Ala Pro Val Gly Pro Asp Glu
130 135 140
Lys Glu Lys Gly Ala Gly Ala Gly Gly Glu Glu Lys Lys Gly Ala Gly
145 150 155 160
Glu Gly Gly Lys Asp Gly Glu Gly Gly Lys Glu Gly Glu Lys Lys Asn
165 170 175
Gly Lys Tyr Glu Lys Pro Pro Phe Ser Tyr Asn Ala Leu Ile Met Met
180 185 190
Ala Ile Arg Gln Ser Pro Glu Lys Arg Leu Thr Leu Asn Gly Ile Tyr
195 200 205
Glu Phe Ile Met Lys Asn Phe Pro Tyr Tyr Arg Glu Asn Lys Gln Gly
210 215 220
Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Lys Cys Phe Val
225 230 235 240
Lys Val Pro Arg His Tyr Asp Asp Pro Gly Lys Gly Asn Tyr Trp Met
245 250 255
Leu Asp Pro Ser Ser Asp Asp Val Phe Ile Gly Gly Thr Thr Gly Lys
260 265 270
Leu Arg Arg Arg Ser Thr Thr Ser Arg Ala Lys Leu Ala Phe Lys Arg
275 280 285
Gly Ala Arg Leu Thr Ser Thr Gly Leu Thr Phe Met Asp Arg Ala Gly
290 295 300
Ser Leu Tyr Trp Pro Met Ser Pro Phe Leu Ser Leu His His Pro Arg
305 310 315 320
Ala Ser Ser Thr Leu Ser Tyr Asn Gly Thr Thr Ser Ala Tyr Pro Ser
325 330 335
His Pro Met Pro Tyr Ser Ser Val Leu Thr Gln Asn Ser Leu Gly Asn
340 345 350
Asn His Ser Phe Ser Thr Ala Asn Gly Leu Ser Val Asp Arg Leu Val
355 360 365
Asn Gly Glu Ile Pro Tyr Ala Thr His His Leu Thr Ala Ala Ala Leu
370 375 380
Ala Ala Ser Val Pro Cys Gly Leu Ser Val Pro Cys Ser Gly Thr Tyr
385 390 395 400
Ser Leu Asn Pro Cys Ser Val Asn Leu Leu Ala Gly Gln Thr Ser Tyr
405 410 415
Phe Phe Pro His Val Pro His Pro Ser Met Thr Ser Gln Ser Ser Thr
420 425 430
Ser Met Ser Ala Arg Ala Ala Ser Ser Ser Thr Ser Pro Gln Ala Pro
435 440 445
Ser Thr Leu Pro Cys Glu Ser Leu Arg Pro Ser Leu Pro Ser Phe Thr
450 455 460
Thr Gly Leu Ser Gly Gly Leu Ser Asp Tyr Phe Thr His Gln Asn Gln
465 470 475 480
Gly Ser Ser Ser Asn Pro Leu Ile His
485
<210> 29
<211> 523
<212> PRT
<213> 人类
<400> 29
Met Ala Gly His Thr Gln Gln Pro Ser Gly Arg Gly Asn Pro Arg Pro
1 5 10 15
Ala Pro Ser Pro Ser Pro Val Pro Gly Thr Val Pro Gly Ala Ser Glu
20 25 30
Arg Val Ala Leu Lys Lys Glu Ile Gly Leu Leu Ser Ala Cys Thr Ile
35 40 45
Ile Ile Gly Asn Ile Ile Gly Ser Gly Ile Phe Ile Ser Pro Lys Gly
50 55 60
Val Leu Glu His Ser Gly Ser Val Gly Leu Ala Leu Phe Val Trp Val
65 70 75 80
Leu Gly Gly Gly Val Thr Ala Leu Gly Ser Leu Cys Tyr Ala Glu Leu
85 90 95
Gly Val Ala Ile Pro Lys Ser Gly Gly Asp Tyr Ala Tyr Val Thr Glu
100 105 110
Ile Phe Gly Gly Leu Ala Gly Phe Leu Leu Leu Trp Ser Ala Val Leu
115 120 125
Ile Met Tyr Pro Thr Ser Leu Ala Val Ile Ser Met Thr Phe Ser Asn
130 135 140
Tyr Val Leu Gln Pro Val Phe Pro Asn Cys Ile Pro Pro Thr Thr Ala
145 150 155 160
Ser Arg Val Leu Ser Met Ala Cys Leu Met Leu Leu Thr Trp Val Asn
165 170 175
Ser Ser Ser Val Arg Trp Ala Thr Arg Ile Gln Asp Met Phe Thr Gly
180 185 190
Gly Lys Leu Leu Ala Leu Ser Leu Ile Ile Gly Val Gly Leu Leu Gln
195 200 205
Ile Phe Gln Gly His Phe Glu Glu Leu Arg Pro Ser Asn Ala Phe Ala
210 215 220
Phe Trp Met Thr Pro Ser Val Gly His Leu Ala Leu Ala Phe Leu Gln
225 230 235 240
Gly Ser Phe Ala Phe Ser Gly Trp Asn Phe Leu Asn Tyr Val Thr Glu
245 250 255
Glu Met Val Asp Ala Arg Lys Asn Leu Pro Arg Ala Ile Phe Ile Ser
260 265 270
Ile Pro Leu Val Thr Phe Val Tyr Thr Phe Thr Asn Ile Ala Tyr Phe
275 280 285
Thr Ala Met Ser Pro Gln Glu Leu Leu Ser Ser Asn Ala Val Ala Val
290 295 300
Thr Phe Gly Glu Lys Leu Leu Gly Tyr Phe Ser Trp Val Met Pro Val
305 310 315 320
Ser Val Ala Leu Ser Thr Phe Gly Gly Ile Asn Gly Tyr Leu Phe Thr
325 330 335
Tyr Ser Arg Leu Cys Phe Ser Gly Ala Arg Glu Gly His Leu Pro Ser
340 345 350
Leu Leu Ala Met Ile His Val Arg His Cys Thr Pro Ile Pro Ala Leu
355 360 365
Leu Val Cys Cys Gly Ala Thr Ala Val Ile Met Leu Val Gly Asp Thr
370 375 380
Tyr Thr Leu Ile Asn Tyr Val Ser Phe Ile Asn Tyr Leu Cys Tyr Gly
385 390 395 400
Val Thr Ile Leu Gly Leu Leu Leu Leu Arg Trp Arg Arg Pro Ala Leu
405 410 415
His Arg Pro Ile Lys Val Asn Leu Leu Ile Pro Val Ala Tyr Leu Val
420 425 430
Phe Trp Ala Phe Leu Leu Val Phe Ser Phe Ile Ser Glu Pro Met Val
435 440 445
Cys Gly Val Gly Val Ile Ile Ile Leu Thr Gly Val Pro Ile Phe Phe
450 455 460
Leu Gly Val Phe Trp Arg Ser Lys Pro Lys Cys Val His Arg Leu Thr
465 470 475 480
Glu Ser Met Thr His Trp Gly Gln Glu Leu Cys Phe Val Val Tyr Pro
485 490 495
Gln Asp Ala Pro Glu Glu Glu Glu Asn Gly Pro Cys Pro Pro Ser Leu
500 505 510
Leu Pro Ala Thr Asp Lys Pro Ser Lys Pro Gln
515 520
<210> 30
<211> 236
<212> PRT
<213> 人类
<400> 30
Met Glu Ser Ser Ala Lys Met Glu Ser Gly Gly Ala Gly Gln Gln Pro
1 5 10 15
Gln Pro Gln Pro Gln Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe
20 25 30
Ala Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln
35 40 45
Ser Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ala Pro
50 55 60
Gln Leu Arg Pro Ala Ala Asp Gly Gln Pro Ser Gly Gly Gly His Lys
65 70 75 80
Ser Ala Pro Lys Gln Val Lys Arg Gln Arg Ser Ser Ser Pro Glu Leu
85 90 95
Met Arg Cys Lys Arg Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu
100 105 110
Pro Gln Gln Gln Pro Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg
115 120 125
Asn Arg Val Lys Leu Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His
130 135 140
Val Pro Asn Gly Ala Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu
145 150 155 160
Arg Ser Ala Val Glu Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu
165 170 175
His Asp Ala Val Ser Ala Ala Phe Gln Ala Gly Val Leu Ser Pro Thr
180 185 190
Ile Ser Pro Asn Tyr Ser Asn Asp Leu Asn Ser Met Ala Gly Ser Pro
195 200 205
Val Ser Ser Tyr Ser Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ser Pro
210 215 220
Glu Glu Gln Glu Leu Leu Asp Phe Thr Asn Trp Phe
225 230 235
<210> 31
<211> 598
<212> PRT
<213> 人类
<400> 31
Met Pro Cys Val Gln Ala Gln Tyr Gly Ser Ser Pro Gln Gly Ala Ser
1 5 10 15
Pro Ala Ser Gln Ser Tyr Ser Tyr His Ser Ser Gly Glu Tyr Ser Ser
20 25 30
Asp Phe Leu Thr Pro Glu Phe Val Lys Phe Ser Met Asp Leu Thr Asn
35 40 45
Thr Glu Ile Thr Ala Thr Thr Ser Leu Pro Ser Phe Ser Thr Phe Met
50 55 60
Asp Asn Tyr Ser Thr Gly Tyr Asp Val Lys Pro Pro Cys Leu Tyr Gln
65 70 75 80
Met Pro Leu Ser Gly Gln Gln Ser Ser Ile Lys Val Glu Asp Ile Gln
85 90 95
Met His Asn Tyr Gln Gln His Ser His Leu Pro Pro Gln Ser Glu Glu
100 105 110
Met Met Pro His Ser Gly Ser Val Tyr Tyr Lys Pro Ser Ser Pro Pro
115 120 125
Thr Pro Thr Thr Pro Gly Phe Gln Val Gln His Ser Pro Met Trp Asp
130 135 140
Asp Pro Gly Ser Leu His Asn Phe His Gln Asn Tyr Val Ala Thr Thr
145 150 155 160
His Met Ile Glu Gln Arg Lys Thr Pro Val Ser Arg Leu Ser Leu Phe
165 170 175
Ser Phe Lys Gln Ser Pro Pro Gly Thr Pro Val Ser Ser Cys Gln Met
180 185 190
Arg Phe Asp Gly Pro Leu His Val Pro Met Asn Pro Glu Pro Ala Gly
195 200 205
Ser His His Val Val Asp Gly Gln Thr Phe Ala Val Pro Asn Pro Ile
210 215 220
Arg Lys Pro Ala Ser Met Gly Phe Pro Gly Leu Gln Ile Gly His Ala
225 230 235 240
Ser Gln Leu Leu Asp Thr Gln Val Pro Ser Pro Pro Ser Arg Gly Ser
245 250 255
Pro Ser Asn Glu Gly Leu Cys Ala Val Cys Gly Asp Asn Ala Ala Cys
260 265 270
Gln His Tyr Gly Val Arg Thr Cys Glu Gly Cys Lys Gly Phe Phe Lys
275 280 285
Arg Thr Val Gln Lys Asn Ala Lys Tyr Val Cys Leu Ala Asn Lys Asn
290 295 300
Cys Pro Val Asp Lys Arg Arg Arg Asn Arg Cys Gln Tyr Cys Arg Phe
305 310 315 320
Gln Lys Cys Leu Ala Val Gly Met Val Lys Glu Val Val Arg Thr Asp
325 330 335
Ser Leu Lys Gly Arg Arg Gly Arg Leu Pro Ser Lys Pro Lys Ser Pro
340 345 350
Gln Glu Pro Ser Pro Pro Ser Pro Pro Val Ser Leu Ile Ser Ala Leu
355 360 365
Val Arg Ala His Val Asp Ser Asn Pro Ala Met Thr Ser Leu Asp Tyr
370 375 380
Ser Arg Phe Gln Ala Asn Pro Asp Tyr Gln Met Ser Gly Asp Asp Thr
385 390 395 400
Gln His Ile Gln Gln Phe Tyr Asp Leu Leu Thr Gly Ser Met Glu Ile
405 410 415
Ile Arg Gly Trp Ala Glu Lys Ile Pro Gly Phe Ala Asp Leu Pro Lys
420 425 430
Ala Asp Gln Asp Leu Leu Phe Glu Ser Ala Phe Leu Glu Leu Phe Val
435 440 445
Leu Arg Leu Ala Tyr Arg Ser Asn Pro Val Glu Gly Lys Leu Ile Phe
450 455 460
Cys Asn Gly Val Val Leu His Arg Leu Gln Cys Val Arg Gly Phe Gly
465 470 475 480
Glu Trp Ile Asp Ser Ile Val Glu Phe Ser Ser Asn Leu Gln Asn Met
485 490 495
Asn Ile Asp Ile Ser Ala Phe Ser Cys Ile Ala Ala Leu Ala Met Val
500 505 510
Thr Glu Arg His Gly Leu Lys Glu Pro Lys Arg Val Glu Glu Leu Gln
515 520 525
Asn Lys Ile Val Asn Cys Leu Lys Asp His Val Thr Phe Asn Asn Gly
530 535 540
Gly Leu Asn Arg Pro Asn Tyr Leu Ser Lys Leu Leu Gly Lys Leu Pro
545 550 555 560
Glu Leu Arg Thr Leu Cys Thr Gln Gly Leu Gln Arg Ile Phe Tyr Leu
565 570 575
Lys Leu Glu Asp Leu Val Pro Pro Pro Ala Ile Ile Asp Lys Leu Phe
580 585 590
Leu Asp Thr Leu Pro Phe
595
<210> 32
<211> 272
<212> PRT
<213> 人类
<400> 32
Met Phe Val Lys Ser Glu Thr Leu Glu Leu Lys Glu Glu Glu Asp Val
1 5 10 15
Leu Val Leu Leu Gly Ser Ala Ser Pro Ala Leu Ala Ala Leu Thr Pro
20 25 30
Leu Ser Ser Ser Ala Asp Glu Glu Glu Glu Glu Glu Pro Gly Ala Ser
35 40 45
Gly Gly Ala Arg Arg Gln Arg Gly Ala Glu Ala Gly Gln Gly Ala Arg
50 55 60
Gly Gly Val Ala Ala Gly Ala Glu Gly Cys Arg Pro Ala Arg Leu Leu
65 70 75 80
Gly Leu Val His Asp Cys Lys Arg Arg Pro Ser Arg Ala Arg Ala Val
85 90 95
Ser Arg Gly Ala Lys Thr Ala Glu Thr Val Gln Arg Ile Lys Lys Thr
100 105 110
Arg Arg Leu Lys Ala Asn Asn Arg Glu Arg Asn Arg Met His Asn Leu
115 120 125
Asn Ala Ala Leu Asp Ala Leu Arg Glu Val Leu Pro Thr Phe Pro Glu
130 135 140
Asp Ala Lys Leu Thr Lys Ile Glu Thr Leu Arg Phe Ala His Asn Tyr
145 150 155 160
Ile Trp Ala Leu Thr Glu Thr Leu Arg Leu Ala Asp His Cys Gly Gly
165 170 175
Gly Gly Gly Gly Leu Pro Gly Ala Leu Phe Ser Glu Ala Val Leu Leu
180 185 190
Ser Pro Gly Gly Ala Ser Ala Ala Leu Ser Ser Ser Gly Asp Ser Pro
195 200 205
Ser Pro Ala Ser Thr Trp Ser Cys Thr Asn Ser Pro Ala Pro Ser Ser
210 215 220
Ser Val Ser Ser Asn Ser Thr Ser Pro Tyr Ser Cys Thr Leu Ser Pro
225 230 235 240
Ala Ser Pro Ala Gly Ser Asp Met Asp Tyr Trp Gln Pro Pro Pro Pro
245 250 255
Asp Lys His Arg Tyr Ala Pro His Leu Pro Ile Ala Arg Asp Cys Ile
260 265 270
<210> 33
<211> 382
<212> PRT
<213> 人类
<400> 33
Met Leu Asp Gly Leu Lys Met Glu Glu Asn Phe Gln Ser Ala Ile Asp
1 5 10 15
Thr Ser Ala Ser Phe Ser Ser Leu Leu Gly Arg Ala Val Ser Pro Lys
20 25 30
Ser Val Cys Glu Gly Cys Gln Arg Val Ile Leu Asp Arg Phe Leu Leu
35 40 45
Arg Leu Asn Asp Ser Phe Trp His Glu Gln Cys Val Gln Cys Ala Ser
50 55 60
Cys Lys Glu Pro Leu Glu Thr Thr Cys Phe Tyr Arg Asp Lys Lys Leu
65 70 75 80
Tyr Cys Lys Tyr Asp Tyr Glu Lys Leu Phe Ala Val Lys Cys Gly Gly
85 90 95
Cys Phe Glu Ala Ile Ala Pro Asn Glu Phe Val Met Arg Ala Gln Lys
100 105 110
Ser Val Tyr His Leu Ser Cys Phe Cys Cys Cys Val Cys Glu Arg Gln
115 120 125
Leu Gln Lys Gly Asp Glu Phe Val Leu Lys Glu Gly Gln Leu Leu Cys
130 135 140
Lys Gly Asp Tyr Glu Lys Glu Arg Glu Leu Leu Ser Leu Val Ser Pro
145 150 155 160
Ala Ala Ser Asp Ser Gly Lys Ser Asp Asp Glu Glu Ser Leu Cys Lys
165 170 175
Ser Ala His Gly Ala Gly Lys Gly Thr Ala Glu Glu Gly Lys Asp His
180 185 190
Lys Arg Pro Lys Arg Pro Arg Thr Ile Leu Thr Thr Gln Gln Arg Arg
195 200 205
Ala Phe Lys Ala Ser Phe Glu Val Ser Ser Lys Pro Cys Arg Lys Val
210 215 220
Arg Glu Thr Leu Ala Ala Glu Thr Gly Leu Ser Val Arg Val Val Gln
225 230 235 240
Val Trp Phe Gln Asn Gln Arg Ala Lys Met Lys Lys Leu Ala Arg Arg
245 250 255
Gln Gln Gln Gln Gln Gln Asp Gln Gln Asn Thr Gln Arg Leu Ser Ser
260 265 270
Ala Gln Thr Asn Gly Gly Gly Ser Ala Gly Met Glu Gly Ile Met Asn
275 280 285
Pro Tyr Thr Ala Leu Pro Thr Pro Gln Gln Leu Leu Ala Ile Glu Gln
290 295 300
Ser Val Tyr Ser Ser Asp Pro Phe Arg Gln Gly Leu Thr Pro Pro Gln
305 310 315 320
Met Pro Gly Asp His Met His Pro Tyr Gly Ala Glu Pro Leu Phe His
325 330 335
Asp Leu Asp Ser Asp Asp Thr Ser Leu Ser Asn Leu Gly Asp Cys Phe
340 345 350
Leu Ala Thr Ser Glu Ala Gly Pro Leu Gln Ser Arg Val Gly Asn Pro
355 360 365
Ile Asp His Leu Tyr Ser Met Gln Asn Ser Tyr Phe Thr Ser
370 375 380
<210> 34
<211> 400
<212> PRT
<213> 人类
<400> 34
Met Glu Lys Ser Lys Asn Phe Arg Ile Glu Pro Cys Trp Arg Trp Thr
1 5 10 15
Pro His Glu Pro Pro Leu Ala Glu Arg Ala Leu Ala Lys Val Thr Ser
20 25 30
Pro Pro Val Pro Ala Ser Gly Thr Gly Gly Gly Gly Gly Gly Gly Gly
35 40 45
Ala Ser Gly Gly Thr Ser Gly Ser Cys Ser Pro Ala Ser Ser Glu Pro
50 55 60
Pro Ala Ala Pro Ala Asp Arg Leu Arg Ala Glu Ser Pro Ser Pro Pro
65 70 75 80
Arg Leu Leu Ala Ala His Cys Ala Leu Leu Pro Lys Pro Gly Phe Leu
85 90 95
Gly Ala Gly Gly Gly Gly Gly Gly Thr Gly Gly Gly His Gly Gly Pro
100 105 110
His His His Ala His Pro Gly Ala Ala Ala Ala Ala Ala Ala Ala Ala
115 120 125
Ala Ala Ala Ala Ala Ala Ala Gly Gly Leu Ala Leu Gly Leu His Pro
130 135 140
Gly Gly Ala Gln Gly Gly Ala Gly Leu Pro Ala Gln Ala Ala Leu Tyr
145 150 155 160
Gly His Pro Val Tyr Gly Tyr Ser Ala Ala Ala Ala Ala Ala Ala Leu
165 170 175
Ala Gly Gln His Pro Ala Leu Ser Tyr Ser Tyr Pro Gln Val Gln Gly
180 185 190
Ala His Pro Ala His Pro Ala Asp Pro Ile Lys Leu Gly Ala Gly Thr
195 200 205
Phe Gln Leu Asp Gln Trp Leu Arg Ala Thr Ala Gly Met Ile Leu Pro
210 215 220
Lys Met Pro Asp Phe Asn Ser Gln Ala Gln Ser Asn Leu Leu Gly Lys
225 230 235 240
Cys Arg Arg Pro Arg Thr Ala Phe Thr Ser Gln Gln Leu Leu Glu Leu
245 250 255
Glu His Gln Phe Lys Phe Asn Lys Tyr Leu Ser Arg Pro Lys Arg Phe
260 265 270
Glu Val Ala Thr Ser Leu Met Leu Thr Glu Thr Gln Val Lys Ile Trp
275 280 285
Phe Gln Asn Arg Arg Met Lys Trp Lys Arg Ser Lys Lys Ala Lys Glu
290 295 300
Gln Ala Ala Gln Glu Ala Glu Lys Gln Lys Gly Gly Gly Gly Gly Ala
305 310 315 320
Gly Lys Gly Gly Ala Glu Glu Pro Gly Ala Glu Glu Leu Leu Gly Pro
325 330 335
Pro Ala Pro Arg Asp Lys Gly Ser Gly Pro Pro Ala Asp Leu Arg Asp
340 345 350
Ser Asp Pro Glu Glu Asp Glu Asp Glu Asp Asp Glu Asp His Phe Pro
355 360 365
Tyr Ser Asn Gly Ala Ser Val His Ala Ala Ser Ser Asp Cys Ser Ser
370 375 380
Glu Asp Asp Ser Pro Pro Pro Arg Pro Ser His Gln Pro Ala Pro Gln
385 390 395 400
<210> 35
<211> 397
<212> PRT
<213> 人类
<400> 35
Met Leu Leu Glu Thr Gly Leu Glu Arg Asp Arg Ala Arg Pro Gly Ala
1 5 10 15
Ala Ala Val Cys Thr Leu Gly Gly Thr Arg Glu Ile Pro Leu Cys Ala
20 25 30
Gly Cys Asp Gln His Ile Leu Asp Arg Phe Ile Leu Lys Ala Leu Asp
35 40 45
Arg His Trp His Ser Lys Cys Leu Lys Cys Ser Asp Cys His Thr Pro
50 55 60
Leu Ala Glu Arg Cys Phe Ser Arg Gly Glu Ser Val Tyr Cys Lys Asp
65 70 75 80
Asp Phe Phe Lys Arg Phe Gly Thr Lys Cys Ala Ala Cys Gln Leu Gly
85 90 95
Ile Pro Pro Thr Gln Val Val Arg Arg Ala Gln Asp Phe Val Tyr His
100 105 110
Leu His Cys Phe Ala Cys Val Val Cys Lys Arg Gln Leu Ala Thr Gly
115 120 125
Asp Glu Phe Tyr Leu Met Glu Asp Ser Arg Leu Val Cys Lys Ala Asp
130 135 140
Tyr Glu Thr Ala Lys Gln Arg Glu Ala Glu Ala Thr Ala Lys Arg Pro
145 150 155 160
Arg Thr Thr Ile Thr Ala Lys Gln Leu Glu Thr Leu Lys Ser Ala Tyr
165 170 175
Asn Thr Ser Pro Lys Pro Ala Arg His Val Arg Glu Gln Leu Ser Ser
180 185 190
Glu Thr Gly Leu Asp Met Arg Val Val Gln Val Trp Phe Gln Asn Arg
195 200 205
Arg Ala Lys Glu Lys Arg Leu Lys Lys Asp Ala Gly Arg Gln Arg Trp
210 215 220
Gly Gln Tyr Phe Arg Asn Met Lys Arg Ser Arg Gly Gly Ser Lys Ser
225 230 235 240
Asp Lys Asp Ser Val Gln Glu Gly Gln Asp Ser Asp Ala Glu Val Ser
245 250 255
Phe Pro Asp Glu Pro Ser Leu Ala Glu Met Gly Pro Ala Asn Gly Leu
260 265 270
Tyr Gly Ser Leu Gly Glu Pro Thr Gln Ala Leu Gly Arg Pro Ser Gly
275 280 285
Ala Leu Gly Asn Phe Ser Leu Glu His Gly Gly Leu Ala Gly Pro Glu
290 295 300
Gln Tyr Arg Glu Leu Arg Pro Gly Ser Pro Tyr Gly Val Pro Pro Ser
305 310 315 320
Pro Ala Ala Pro Gln Ser Leu Pro Gly Pro Gln Pro Leu Leu Ser Ser
325 330 335
Leu Val Tyr Pro Asp Thr Ser Leu Gly Leu Val Pro Ser Gly Ala Pro
340 345 350
Gly Gly Pro Pro Pro Met Arg Val Leu Ala Gly Asn Gly Pro Ser Ser
355 360 365
Asp Leu Ser Thr Gly Ser Ser Gly Gly Tyr Pro Asp Phe Pro Ala Ser
370 375 380
Pro Ala Ser Trp Leu Asp Glu Val Asp His Ala Gln Phe
385 390 395
<210> 36
<211> 328
<212> PRT
<213> 人类
<400> 36
Met Thr Gly Val Phe Asp Ser Leu Val Ala Asp Met His Ser Thr Gln
1 5 10 15
Ile Ala Ala Ser Ser Thr Tyr His Gln His Gln Gln Pro Pro Ser Gly
20 25 30
Gly Gly Ala Gly Pro Gly Gly Asn Ser Ser Ser Ser Ser Ser Leu His
35 40 45
Lys Pro Gln Glu Ser Pro Thr Leu Pro Val Ser Thr Ala Thr Asp Ser
50 55 60
Ser Tyr Tyr Thr Asn Gln Gln His Pro Ala Gly Gly Gly Gly Gly Gly
65 70 75 80
Gly Ser Pro Tyr Ala His Met Gly Ser Tyr Gln Tyr Gln Ala Ser Gly
85 90 95
Leu Asn Asn Val Pro Tyr Ser Ala Lys Ser Ser Tyr Asp Leu Gly Tyr
100 105 110
Thr Ala Ala Tyr Thr Ser Tyr Ala Pro Tyr Gly Thr Ser Ser Ser Pro
115 120 125
Ala Asn Asn Glu Pro Glu Lys Glu Asp Leu Glu Pro Glu Ile Arg Ile
130 135 140
Val Asn Gly Lys Pro Lys Lys Val Arg Lys Pro Arg Thr Ile Tyr Ser
145 150 155 160
Ser Phe Gln Leu Ala Ala Leu Gln Arg Arg Phe Gln Lys Thr Gln Tyr
165 170 175
Leu Ala Leu Pro Glu Arg Ala Glu Leu Ala Ala Ser Leu Gly Leu Thr
180 185 190
Gln Thr Gln Val Lys Ile Trp Phe Gln Asn Arg Arg Ser Lys Phe Lys
195 200 205
Lys Met Trp Lys Ser Gly Glu Ile Pro Ser Glu Gln His Pro Gly Ala
210 215 220
Ser Ala Ser Pro Pro Cys Ala Ser Pro Pro Val Ser Ala Pro Ala Ser
225 230 235 240
Trp Asp Phe Gly Val Pro Gln Arg Met Ala Gly Gly Gly Gly Pro Gly
245 250 255
Ser Gly Gly Ser Gly Ala Gly Ser Ser Gly Ser Ser Pro Ser Ser Ala
260 265 270
Ala Ser Ala Phe Leu Gly Asn Tyr Pro Trp Tyr His Gln Thr Ser Gly
275 280 285
Ser Ala Ser His Leu Gln Ala Thr Ala Pro Leu Leu His Pro Thr Gln
290 295 300
Thr Pro Gln Pro His His His His His His His Gly Gly Gly Gly Ala
305 310 315 320
Pro Val Ser Ala Gly Thr Ile Phe
325
<210> 37
<211> 521
<212> PRT
<213> 人类
<400> 37
Met Ala Ser Asn Ser Leu Phe Ser Thr Val Thr Pro Cys Gln Gln Asn
1 5 10 15
Phe Phe Trp Asp Pro Ser Thr Ser Arg Arg Phe Ser Pro Pro Ser Ser
20 25 30
Ser Leu Gln Pro Gly Lys Met Ser Asp Val Ser Pro Val Val Ala Ala
35 40 45
Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln
50 55 60
Gln Gln Gln Gln Gln Gln Gln Glu Ala Ala Ala Ala Ala Ala Ala Ala
65 70 75 80
Ala Ala Ala Ala Ala Ala Ala Ala Ala Val Pro Arg Leu Arg Pro Pro
85 90 95
His Asp Asn Arg Thr Met Val Glu Ile Ile Ala Asp His Pro Ala Glu
100 105 110
Leu Val Arg Thr Asp Ser Pro Asn Phe Leu Cys Ser Val Leu Pro Ser
115 120 125
His Trp Arg Cys Asn Lys Thr Leu Pro Val Ala Phe Lys Val Val Ala
130 135 140
Leu Gly Glu Val Pro Asp Gly Thr Val Val Thr Val Met Ala Gly Asn
145 150 155 160
Asp Glu Asn Tyr Ser Ala Glu Leu Arg Asn Ala Ser Ala Val Met Lys
165 170 175
Asn Gln Val Ala Arg Phe Asn Asp Leu Arg Phe Val Gly Arg Ser Gly
180 185 190
Arg Gly Lys Ser Phe Thr Leu Thr Ile Thr Val Phe Thr Asn Pro Pro
195 200 205
Gln Val Ala Thr Tyr His Arg Ala Ile Lys Val Thr Val Asp Gly Pro
210 215 220
Arg Glu Pro Arg Arg His Arg Gln Lys Leu Asp Asp Ser Lys Pro Ser
225 230 235 240
Leu Phe Ser Asp Arg Leu Ser Asp Leu Gly Arg Ile Pro His Pro Ser
245 250 255
Met Arg Val Gly Val Pro Pro Gln Asn Pro Arg Pro Ser Leu Asn Ser
260 265 270
Ala Pro Ser Pro Phe Asn Pro Gln Gly Gln Ser Gln Ile Thr Asp Pro
275 280 285
Arg Gln Ala Gln Ser Ser Pro Pro Trp Ser Tyr Asp Gln Ser Tyr Pro
290 295 300
Ser Tyr Leu Ser Gln Met Thr Ser Pro Ser Ile His Ser Thr Thr Pro
305 310 315 320
Leu Ser Ser Thr Arg Gly Thr Gly Leu Pro Ala Ile Thr Asp Val Pro
325 330 335
Arg Arg Ile Ser Asp Asp Asp Thr Ala Thr Ser Asp Phe Cys Leu Trp
340 345 350
Pro Ser Thr Leu Ser Lys Lys Ser Gln Ala Gly Ala Ser Glu Leu Gly
355 360 365
Pro Phe Ser Asp Pro Arg Gln Phe Pro Ser Ile Ser Ser Leu Thr Glu
370 375 380
Ser Arg Phe Ser Asn Pro Arg Met His Tyr Pro Ala Thr Phe Thr Tyr
385 390 395 400
Thr Pro Pro Val Thr Ser Gly Met Ser Leu Gly Met Ser Ala Thr Thr
405 410 415
His Tyr His Thr Tyr Leu Pro Pro Pro Tyr Pro Gly Ser Ser Gln Ser
420 425 430
Gln Ser Gly Pro Phe Gln Thr Ser Ser Thr Pro Tyr Leu Tyr Tyr Gly
435 440 445
Thr Ser Ser Gly Ser Tyr Gln Phe Pro Met Val Pro Gly Gly Asp Arg
450 455 460
Ser Pro Ser Arg Met Leu Pro Pro Cys Thr Thr Thr Ser Asn Gly Ser
465 470 475 480
Thr Leu Leu Asn Pro Asn Leu Pro Asn Gln Asn Asp Gly Val Asp Ala
485 490 495
Asp Gly Ser His Ser Ser Ser Pro Thr Val Leu Asn Ser Ser Gly Arg
500 505 510
Met Asp Glu Ser Val Trp Arg Pro Tyr
515 520
<210> 38
<211> 763
<212> PRT
<213> 人类
<400> 38
Met Leu Thr Asp Pro Asp Leu Pro Gln Glu Phe Glu Arg Met Ser Ser
1 5 10 15
Lys Arg Pro Ala Ser Pro Tyr Gly Glu Ala Asp Gly Glu Val Ala Met
20 25 30
Val Thr Ser Arg Gln Lys Val Glu Glu Glu Glu Ser Asp Gly Leu Pro
35 40 45
Ala Phe His Leu Pro Leu His Val Ser Phe Pro Asn Lys Pro His Ser
50 55 60
Glu Glu Phe Gln Pro Val Ser Leu Leu Thr Gln Glu Thr Cys Gly His
65 70 75 80
Arg Thr Pro Thr Ser Gln His Asn Thr Met Glu Val Asp Gly Asn Lys
85 90 95
Val Met Ser Ser Phe Ala Pro His Asn Ser Ser Thr Ser Pro Gln Lys
100 105 110
Ala Glu Glu Gly Gly Arg Gln Ser Gly Glu Ser Leu Ser Ser Thr Ala
115 120 125
Leu Gly Thr Pro Glu Arg Arg Lys Gly Ser Leu Ala Asp Val Val Asp
130 135 140
Thr Leu Lys Gln Arg Lys Met Glu Glu Leu Ile Lys Asn Glu Pro Glu
145 150 155 160
Glu Thr Pro Ser Ile Glu Lys Leu Leu Ser Lys Asp Trp Lys Asp Lys
165 170 175
Leu Leu Ala Met Gly Ser Gly Asn Phe Gly Glu Ile Lys Gly Thr Pro
180 185 190
Glu Ser Leu Ala Glu Lys Glu Arg Gln Leu Met Gly Met Ile Asn Gln
195 200 205
Leu Thr Ser Leu Arg Glu Gln Leu Leu Ala Ala His Asp Glu Gln Lys
210 215 220
Lys Leu Ala Ala Ser Gln Ile Glu Lys Gln Arg Gln Gln Met Glu Leu
225 230 235 240
Ala Lys Gln Gln Gln Glu Gln Ile Ala Arg Gln Gln Gln Gln Leu Leu
245 250 255
Gln Gln Gln His Lys Ile Asn Leu Leu Gln Gln Gln Ile Gln Val Gln
260 265 270
Gly Gln Leu Pro Pro Leu Met Ile Pro Val Phe Pro Pro Asp Gln Arg
275 280 285
Thr Leu Ala Ala Ala Ala Gln Gln Gly Phe Leu Leu Pro Pro Gly Phe
290 295 300
Ser Tyr Lys Ala Gly Cys Ser Asp Pro Tyr Pro Val Gln Leu Ile Pro
305 310 315 320
Thr Thr Met Ala Ala Ala Ala Ala Ala Thr Pro Gly Leu Gly Pro Leu
325 330 335
Gln Leu Gln Gln Leu Tyr Ala Ala Gln Leu Ala Ala Met Gln Val Ser
340 345 350
Pro Gly Gly Lys Leu Pro Gly Ile Pro Gln Gly Asn Leu Gly Ala Ala
355 360 365
Val Ser Pro Thr Ser Ile His Thr Asp Lys Ser Thr Asn Ser Pro Pro
370 375 380
Pro Lys Ser Lys Asp Glu Val Ala Gln Pro Leu Asn Leu Ser Ala Lys
385 390 395 400
Pro Lys Thr Ser Asp Gly Lys Ser Pro Thr Ser Pro Thr Ser Pro His
405 410 415
Met Pro Ala Leu Arg Ile Asn Ser Gly Ala Gly Pro Leu Lys Ala Ser
420 425 430
Val Pro Ala Ala Leu Ala Ser Pro Ser Ala Arg Val Ser Thr Ile Gly
435 440 445
Tyr Leu Asn Asp His Asp Ala Val Thr Lys Ala Ile Gln Glu Ala Arg
450 455 460
Gln Met Lys Glu Gln Leu Arg Arg Glu Gln Gln Val Leu Asp Gly Lys
465 470 475 480
Val Ala Val Val Asn Ser Leu Gly Leu Asn Asn Cys Arg Thr Glu Lys
485 490 495
Glu Lys Thr Thr Leu Glu Ser Leu Thr Gln Gln Leu Ala Val Lys Gln
500 505 510
Asn Glu Glu Gly Lys Phe Ser His Ala Met Met Asp Phe Asn Leu Ser
515 520 525
Gly Asp Ser Asp Gly Ser Ala Gly Val Ser Glu Ser Arg Ile Tyr Arg
530 535 540
Glu Ser Arg Gly Arg Gly Ser Asn Glu Pro His Ile Lys Arg Pro Met
545 550 555 560
Asn Ala Phe Met Val Trp Ala Lys Asp Glu Arg Arg Lys Ile Leu Gln
565 570 575
Ala Phe Pro Asp Met His Asn Ser Asn Ile Ser Lys Ile Leu Gly Ser
580 585 590
Arg Trp Lys Ala Met Thr Asn Leu Glu Lys Gln Pro Tyr Tyr Glu Glu
595 600 605
Gln Ala Arg Leu Ser Lys Gln His Leu Glu Lys Tyr Pro Asp Tyr Lys
610 615 620
Tyr Lys Pro Arg Pro Lys Arg Thr Cys Leu Val Asp Gly Lys Lys Leu
625 630 635 640
Arg Ile Gly Glu Tyr Lys Ala Ile Met Arg Asn Arg Arg Gln Glu Met
645 650 655
Arg Gln Tyr Phe Asn Val Gly Gln Gln Ala Gln Ile Pro Ile Ala Thr
660 665 670
Ala Gly Val Val Tyr Pro Gly Ala Ile Ala Met Ala Gly Met Pro Ser
675 680 685
Pro His Leu Pro Ser Glu His Ser Ser Val Ser Ser Ser Pro Glu Pro
690 695 700
Gly Met Pro Val Ile Gln Ser Thr Tyr Gly Val Lys Gly Glu Glu Pro
705 710 715 720
His Ile Lys Glu Glu Ile Gln Ala Glu Asp Ile Asn Gly Glu Ile Tyr
725 730 735
Asp Glu Tyr Asp Glu Glu Glu Asp Asp Pro Asp Val Asp Tyr Gly Ser
740 745 750
Asp Ser Glu Asn His Ile Ala Gly Gln Ala Asn
755 760
<210> 39
<211> 808
<212> PRT
<213> 人类
<400> 39
Met Ser Ser Lys Gln Ala Thr Ser Pro Phe Ala Cys Ala Ala Asp Gly
1 5 10 15
Glu Asp Ala Met Thr Gln Asp Leu Thr Ser Arg Glu Lys Glu Glu Gly
20 25 30
Ser Asp Gln His Val Ala Ser His Leu Pro Leu His Pro Ile Met His
35 40 45
Asn Lys Pro His Ser Glu Glu Leu Pro Thr Leu Val Ser Thr Ile Gln
50 55 60
Gln Asp Ala Asp Trp Asp Ser Val Leu Ser Ser Gln Gln Arg Met Glu
65 70 75 80
Ser Glu Asn Asn Lys Leu Cys Ser Leu Tyr Ser Phe Arg Asn Thr Ser
85 90 95
Thr Ser Pro His Lys Pro Asp Glu Gly Ser Arg Asp Arg Glu Ile Met
100 105 110
Thr Ser Val Thr Phe Gly Thr Pro Glu Arg Arg Lys Gly Ser Leu Ala
115 120 125
Asp Val Val Asp Thr Leu Lys Gln Lys Lys Leu Glu Glu Met Thr Arg
130 135 140
Thr Glu Gln Glu Asp Ser Ser Cys Met Glu Lys Leu Leu Ser Lys Asp
145 150 155 160
Trp Lys Glu Lys Met Glu Arg Leu Asn Thr Ser Glu Leu Leu Gly Glu
165 170 175
Ile Lys Gly Thr Pro Glu Ser Leu Ala Glu Lys Glu Arg Gln Leu Ser
180 185 190
Thr Met Ile Thr Gln Leu Ile Ser Leu Arg Glu Gln Leu Leu Ala Ala
195 200 205
His Asp Glu Gln Lys Lys Leu Ala Ala Ser Gln Ile Glu Lys Gln Arg
210 215 220
Gln Gln Met Asp Leu Ala Arg Gln Gln Gln Glu Gln Ile Ala Arg Gln
225 230 235 240
Gln Gln Gln Leu Leu Gln Gln Gln His Lys Ile Asn Leu Leu Gln Gln
245 250 255
Gln Ile Gln Val Gln Gly His Met Pro Pro Leu Met Ile Pro Ile Phe
260 265 270
Pro His Asp Gln Arg Thr Leu Ala Ala Ala Ala Ala Ala Gln Gln Gly
275 280 285
Phe Leu Phe Pro Pro Gly Ile Thr Tyr Lys Pro Gly Asp Asn Tyr Pro
290 295 300
Val Gln Phe Ile Pro Ser Thr Met Ala Ala Ala Ala Ala Ser Gly Leu
305 310 315 320
Ser Pro Leu Gln Leu Gln Lys Gly His Ala Ser His Pro Gln Ile Asn
325 330 335
Gln Arg Leu Lys Gly Leu Ser Asp Arg Phe Gly Arg Asn Leu Asp Thr
340 345 350
Phe Glu His Gly Gly Gly His Ser Tyr Asn His Lys Gln Ile Glu Gln
355 360 365
Leu Tyr Ala Ala Gln Leu Ala Ser Met Gln Val Ser Pro Gly Ala Lys
370 375 380
Met Pro Ser Thr Pro Gln Pro Pro Asn Thr Ala Gly Thr Val Ser Pro
385 390 395 400
Thr Gly Ile Lys Asn Glu Lys Arg Gly Thr Ser Pro Val Thr Gln Val
405 410 415
Lys Asp Glu Ala Ala Ala Gln Pro Leu Asn Leu Ser Ser Arg Pro Lys
420 425 430
Thr Ala Glu Pro Val Lys Ser Pro Thr Ser Pro Thr Gln Asn Leu Phe
435 440 445
Pro Ala Ser Lys Thr Ser Pro Val Asn Leu Pro Asn Lys Ser Ser Ile
450 455 460
Pro Ser Pro Ile Gly Gly Ser Leu Gly Arg Gly Ser Ser Leu Asp Ile
465 470 475 480
Leu Ser Ser Leu Asn Ser Pro Ala Leu Phe Gly Asp Gln Asp Thr Val
485 490 495
Met Lys Ala Ile Gln Glu Ala Arg Lys Met Arg Glu Gln Ile Gln Arg
500 505 510
Glu Gln Gln Gln Gln Gln Pro His Gly Val Asp Gly Lys Leu Ser Ser
515 520 525
Ile Asn Asn Met Gly Leu Asn Ser Cys Arg Asn Glu Lys Glu Arg Thr
530 535 540
Arg Phe Glu Asn Leu Gly Pro Gln Leu Thr Gly Lys Ser Asn Glu Asp
545 550 555 560
Gly Lys Leu Gly Pro Gly Val Ile Asp Leu Thr Arg Pro Glu Asp Ala
565 570 575
Glu Gly Gly Ala Thr Val Ala Glu Ala Arg Val Tyr Arg Asp Ala Arg
580 585 590
Gly Arg Ala Ser Ser Glu Pro His Ile Lys Arg Pro Met Asn Ala Phe
595 600 605
Met Val Trp Ala Lys Asp Glu Arg Arg Lys Ile Leu Gln Ala Phe Pro
610 615 620
Asp Met His Asn Ser Asn Ile Ser Lys Ile Leu Gly Ser Arg Trp Lys
625 630 635 640
Ser Met Ser Asn Gln Glu Lys Gln Pro Tyr Tyr Glu Glu Gln Ala Arg
645 650 655
Leu Ser Lys Ile His Leu Glu Lys Tyr Pro Asn Tyr Lys Tyr Lys Pro
660 665 670
Arg Pro Lys Arg Thr Cys Ile Val Asp Gly Lys Lys Leu Arg Ile Gly
675 680 685
Glu Tyr Lys Gln Leu Met Arg Ser Arg Arg Gln Glu Met Arg Gln Phe
690 695 700
Phe Thr Val Gly Gln Gln Pro Gln Ile Pro Ile Thr Thr Gly Thr Gly
705 710 715 720
Val Val Tyr Pro Gly Ala Ile Thr Met Ala Thr Thr Thr Pro Ser Pro
725 730 735
Gln Met Thr Ser Asp Cys Ser Ser Thr Ser Ala Ser Pro Glu Pro Ser
740 745 750
Leu Pro Val Ile Gln Ser Thr Tyr Gly Met Lys Thr Asp Gly Gly Ser
755 760 765
Leu Ala Gly Asn Glu Met Ile Asn Gly Glu Asp Glu Met Glu Met Tyr
770 775 780
Asp Asp Tyr Glu Asp Asp Pro Lys Ser Asp Tyr Ser Ser Glu Asn Glu
785 790 795 800
Ala Pro Glu Ala Val Ser Ala Asn
805
<210> 40
<211> 595
<212> PRT
<213> 人类
<400> 40
Met Ala Leu Thr Asp Gly Gly Trp Cys Leu Pro Lys Arg Phe Gly Ala
1 5 10 15
Ala Gly Ala Asp Ala Ser Asp Ser Arg Ala Phe Pro Ala Arg Glu Pro
20 25 30
Ser Thr Pro Pro Ser Pro Ile Ser Ser Ser Ser Ser Ser Cys Ser Arg
35 40 45
Gly Gly Glu Arg Gly Pro Gly Gly Ala Ser Asn Cys Gly Thr Pro Gln
50 55 60
Leu Asp Thr Glu Ala Ala Ala Gly Pro Pro Ala Arg Ser Leu Leu Leu
65 70 75 80
Ser Ser Tyr Ala Ser His Pro Phe Gly Ala Pro His Gly Pro Ser Ala
85 90 95
Pro Gly Val Ala Gly Pro Gly Gly Asn Leu Ser Ser Trp Glu Asp Leu
100 105 110
Leu Leu Phe Thr Asp Leu Asp Gln Ala Ala Thr Ala Ser Lys Leu Leu
115 120 125
Trp Ser Ser Arg Gly Ala Lys Leu Ser Pro Phe Ala Pro Glu Gln Pro
130 135 140
Glu Glu Met Tyr Gln Thr Leu Ala Ala Leu Ser Ser Gln Gly Pro Ala
145 150 155 160
Ala Tyr Asp Gly Ala Pro Gly Gly Phe Val His Ser Ala Ala Ala Ala
165 170 175
Ala Ala Ala Ala Ala Ala Ala Ser Ser Pro Val Tyr Val Pro Thr Thr
180 185 190
Arg Val Gly Ser Met Leu Pro Gly Leu Pro Tyr His Leu Gln Gly Ser
195 200 205
Gly Ser Gly Pro Ala Asn His Ala Gly Gly Ala Gly Ala His Pro Gly
210 215 220
Trp Pro Gln Ala Ser Ala Asp Ser Pro Pro Tyr Gly Ser Gly Gly Gly
225 230 235 240
Ala Ala Gly Gly Gly Ala Ala Gly Pro Gly Gly Ala Gly Ser Ala Ala
245 250 255
Ala His Val Ser Ala Arg Phe Pro Tyr Ser Pro Ser Pro Pro Met Ala
260 265 270
Asn Gly Ala Ala Arg Glu Pro Gly Gly Tyr Ala Ala Ala Gly Ser Gly
275 280 285
Gly Ala Gly Gly Val Ser Gly Gly Gly Ser Ser Leu Ala Ala Met Gly
290 295 300
Gly Arg Glu Pro Gln Tyr Ser Ser Leu Ser Ala Ala Arg Pro Leu Asn
305 310 315 320
Gly Thr Tyr His His His His His His His His His His Pro Ser Pro
325 330 335
Tyr Ser Pro Tyr Val Gly Ala Pro Leu Thr Pro Ala Trp Pro Ala Gly
340 345 350
Pro Phe Glu Thr Pro Val Leu His Ser Leu Gln Ser Arg Ala Gly Ala
355 360 365
Pro Leu Pro Val Pro Arg Gly Pro Ser Ala Asp Leu Leu Glu Asp Leu
370 375 380
Ser Glu Ser Arg Glu Cys Val Asn Cys Gly Ser Ile Gln Thr Pro Leu
385 390 395 400
Trp Arg Arg Asp Gly Thr Gly His Tyr Leu Cys Asn Ala Cys Gly Leu
405 410 415
Tyr Ser Lys Met Asn Gly Leu Ser Arg Pro Leu Ile Lys Pro Gln Lys
420 425 430
Arg Val Pro Ser Ser Arg Arg Leu Gly Leu Ser Cys Ala Asn Cys His
435 440 445
Thr Thr Thr Thr Thr Leu Trp Arg Arg Asn Ala Glu Gly Glu Pro Val
450 455 460
Cys Asn Ala Cys Gly Leu Tyr Met Lys Leu His Gly Val Pro Arg Pro
465 470 475 480
Leu Ala Met Lys Lys Glu Gly Ile Gln Thr Arg Lys Arg Lys Pro Lys
485 490 495
Asn Ile Asn Lys Ser Lys Thr Cys Ser Gly Asn Ser Asn Asn Ser Ile
500 505 510
Pro Met Thr Pro Thr Ser Thr Ser Ser Asn Ser Asp Asp Cys Ser Lys
515 520 525
Asn Thr Ser Pro Thr Thr Gln Pro Thr Ala Ser Gly Ala Gly Ala Pro
530 535 540
Val Met Thr Gly Ala Gly Glu Ser Thr Asn Pro Glu Asn Ser Glu Leu
545 550 555 560
Lys Tyr Ser Gly Gln Asp Gly Leu Tyr Ile Gly Val Ser Leu Ala Ser
565 570 575
Pro Ala Glu Val Thr Ser Ser Val Arg Pro Asp Ser Trp Cys Ala Leu
580 585 590
Ala Leu Ala
595
<210> 41
<211> 413
<212> PRT
<213> 人类
<400> 41
Met Glu Phe Pro Gly Leu Gly Ser Leu Gly Thr Ser Glu Pro Leu Pro
1 5 10 15
Gln Phe Val Asp Pro Ala Leu Val Ser Ser Thr Pro Glu Ser Gly Val
20 25 30
Phe Phe Pro Ser Gly Pro Glu Gly Leu Asp Ala Ala Ala Ser Ser Thr
35 40 45
Ala Pro Ser Thr Ala Thr Ala Ala Ala Ala Ala Leu Ala Tyr Tyr Arg
50 55 60
Asp Ala Glu Ala Tyr Arg His Ser Pro Val Phe Gln Val Tyr Pro Leu
65 70 75 80
Leu Asn Cys Met Glu Gly Ile Pro Gly Gly Ser Pro Tyr Ala Gly Trp
85 90 95
Ala Tyr Gly Lys Thr Gly Leu Tyr Pro Ala Ser Thr Val Cys Pro Thr
100 105 110
Arg Glu Asp Ser Pro Pro Gln Ala Val Glu Asp Leu Asp Gly Lys Gly
115 120 125
Ser Thr Ser Phe Leu Glu Thr Leu Lys Thr Glu Arg Leu Ser Pro Asp
130 135 140
Leu Leu Thr Leu Gly Pro Ala Leu Pro Ser Ser Leu Pro Val Pro Asn
145 150 155 160
Ser Ala Tyr Gly Gly Pro Asp Phe Ser Ser Thr Phe Phe Ser Pro Thr
165 170 175
Gly Ser Pro Leu Asn Ser Ala Ala Tyr Ser Ser Pro Lys Leu Arg Gly
180 185 190
Thr Leu Pro Leu Pro Pro Cys Glu Ala Arg Glu Cys Val Asn Cys Gly
195 200 205
Ala Thr Ala Thr Pro Leu Trp Arg Arg Asp Arg Thr Gly His Tyr Leu
210 215 220
Cys Asn Ala Cys Gly Leu Tyr His Lys Met Asn Gly Gln Asn Arg Pro
225 230 235 240
Leu Ile Arg Pro Lys Lys Arg Leu Ile Val Ser Lys Arg Ala Gly Thr
245 250 255
Gln Cys Thr Asn Cys Gln Thr Thr Thr Thr Thr Leu Trp Arg Arg Asn
260 265 270
Ala Ser Gly Asp Pro Val Cys Asn Ala Cys Gly Leu Tyr Tyr Lys Leu
275 280 285
His Gln Val Asn Arg Pro Leu Thr Met Arg Lys Asp Gly Ile Gln Thr
290 295 300
Arg Asn Arg Lys Ala Ser Gly Lys Gly Lys Lys Lys Arg Gly Ser Ser
305 310 315 320
Leu Gly Gly Thr Gly Ala Ala Glu Gly Pro Ala Gly Gly Phe Met Val
325 330 335
Val Ala Gly Gly Ser Gly Ser Gly Asn Cys Gly Glu Val Ala Ser Gly
340 345 350
Leu Thr Leu Gly Pro Pro Gly Thr Ala His Leu Tyr Gln Gly Leu Gly
355 360 365
Pro Val Val Leu Ser Gly Pro Val Ser His Leu Met Pro Phe Pro Gly
370 375 380
Pro Leu Leu Gly Ser Pro Thr Gly Ser Phe Pro Thr Gly Pro Met Pro
385 390 395 400
Pro Thr Thr Ser Thr Thr Val Val Ala Pro Leu Ser Ser
405 410
<210> 42
<211> 452
<212> PRT
<213> 人类
<400> 42
Met Asp Gly Thr Ile Lys Glu Ala Leu Ser Val Val Ser Asp Asp Gln
1 5 10 15
Ser Leu Phe Asp Ser Ala Tyr Gly Ala Ala Ala His Leu Pro Lys Ala
20 25 30
Asp Met Thr Ala Ser Gly Ser Pro Asp Tyr Gly Gln Pro His Lys Ile
35 40 45
Asn Pro Leu Pro Pro Gln Gln Glu Trp Ile Asn Gln Pro Val Arg Val
50 55 60
Asn Val Lys Arg Glu Tyr Asp His Met Asn Gly Ser Arg Glu Ser Pro
65 70 75 80
Val Asp Cys Ser Val Ser Lys Cys Ser Lys Leu Val Gly Gly Gly Glu
85 90 95
Ser Asn Pro Met Asn Tyr Asn Ser Tyr Met Asp Glu Lys Asn Gly Pro
100 105 110
Pro Pro Pro Asn Met Thr Thr Asn Glu Arg Arg Val Ile Val Pro Ala
115 120 125
Asp Pro Thr Leu Trp Thr Gln Glu His Val Arg Gln Trp Leu Glu Trp
130 135 140
Ala Ile Lys Glu Tyr Ser Leu Met Glu Ile Asp Thr Ser Phe Phe Gln
145 150 155 160
Asn Met Asp Gly Lys Glu Leu Cys Lys Met Asn Lys Glu Asp Phe Leu
165 170 175
Arg Ala Thr Thr Leu Tyr Asn Thr Glu Val Leu Leu Ser His Leu Ser
180 185 190
Tyr Leu Arg Glu Ser Ser Leu Leu Ala Tyr Asn Thr Thr Ser His Thr
195 200 205
Asp Gln Ser Ser Arg Leu Ser Val Lys Glu Asp Pro Ser Tyr Asp Ser
210 215 220
Val Arg Arg Gly Ala Trp Gly Asn Asn Met Asn Ser Gly Leu Asn Lys
225 230 235 240
Ser Pro Pro Leu Gly Gly Ala Gln Thr Ile Ser Lys Asn Thr Glu Gln
245 250 255
Arg Pro Gln Pro Asp Pro Tyr Gln Ile Leu Gly Pro Thr Ser Ser Arg
260 265 270
Leu Ala Asn Pro Gly Ser Gly Gln Ile Gln Leu Trp Gln Phe Leu Leu
275 280 285
Glu Leu Leu Ser Asp Ser Ala Asn Ala Ser Cys Ile Thr Trp Glu Gly
290 295 300
Thr Asn Gly Glu Phe Lys Met Thr Asp Pro Asp Glu Val Ala Arg Arg
305 310 315 320
Trp Gly Glu Arg Lys Ser Lys Pro Asn Met Asn Tyr Asp Lys Leu Ser
325 330 335
Arg Ala Leu Arg Tyr Tyr Tyr Asp Lys Asn Ile Met Thr Lys Val His
340 345 350
Gly Lys Arg Tyr Ala Tyr Lys Phe Asp Phe His Gly Ile Ala Gln Ala
355 360 365
Leu Gln Pro His Pro Thr Glu Ser Ser Met Tyr Lys Tyr Pro Ser Asp
370 375 380
Ile Ser Tyr Met Pro Ser Tyr His Ala His Gln Gln Lys Val Asn Phe
385 390 395 400
Val Pro Pro His Pro Ser Ser Met Pro Val Thr Ser Ser Ser Phe Phe
405 410 415
Gly Ala Ala Ser Gln Tyr Trp Thr Ser Pro Thr Gly Gly Ile Tyr Pro
420 425 430
Asn Pro Asn Val Pro Arg His Pro Asn Thr His Val Pro Ser His Leu
435 440 445
Gly Ser Tyr Tyr
450
<210> 43
<211> 362
<212> PRT
<213> 人类
<400> 43
Met Ala Thr Ala Glu Thr Ala Leu Pro Ser Ile Ser Thr Leu Thr Ala
1 5 10 15
Leu Gly Pro Phe Pro Asp Thr Gln Asp Asp Phe Leu Lys Trp Trp Arg
20 25 30
Ser Glu Glu Ala Gln Asp Met Gly Pro Gly Pro Pro Asp Pro Thr Glu
35 40 45
Pro Pro Leu His Val Lys Ser Glu Asp Gln Pro Gly Glu Glu Glu Asp
50 55 60
Asp Glu Arg Gly Ala Asp Ala Thr Trp Asp Leu Asp Leu Leu Leu Thr
65 70 75 80
Asn Phe Ser Gly Pro Glu Pro Gly Gly Ala Pro Gln Thr Cys Ala Leu
85 90 95
Ala Pro Ser Glu Ala Ser Gly Ala Gln Tyr Pro Pro Pro Pro Glu Thr
100 105 110
Leu Gly Ala Tyr Ala Gly Gly Pro Gly Leu Val Ala Gly Leu Leu Gly
115 120 125
Ser Glu Asp His Ser Gly Trp Val Arg Pro Ala Leu Arg Ala Arg Ala
130 135 140
Pro Asp Ala Phe Val Gly Pro Ala Leu Ala Pro Ala Pro Ala Pro Glu
145 150 155 160
Pro Lys Ala Leu Ala Leu Gln Pro Val Tyr Pro Gly Pro Gly Ala Gly
165 170 175
Ser Ser Gly Gly Tyr Phe Pro Arg Thr Gly Leu Ser Val Pro Ala Ala
180 185 190
Ser Gly Ala Pro Tyr Gly Leu Leu Ser Gly Tyr Pro Ala Met Tyr Pro
195 200 205
Ala Pro Gln Tyr Gln Gly His Phe Gln Leu Phe Arg Gly Leu Gln Gly
210 215 220
Pro Ala Pro Gly Pro Ala Thr Ser Pro Ser Phe Leu Ser Cys Leu Gly
225 230 235 240
Pro Gly Thr Val Gly Thr Gly Leu Gly Gly Thr Ala Glu Asp Pro Gly
245 250 255
Val Ile Ala Glu Thr Ala Pro Ser Lys Arg Gly Arg Arg Ser Trp Ala
260 265 270
Arg Lys Arg Gln Ala Ala His Thr Cys Ala His Pro Gly Cys Gly Lys
275 280 285
Ser Tyr Thr Lys Ser Ser His Leu Lys Ala His Leu Arg Thr His Thr
290 295 300
Gly Glu Lys Pro Tyr Ala Cys Thr Trp Glu Gly Cys Gly Trp Arg Phe
305 310 315 320
Ala Arg Ser Asp Glu Leu Thr Arg His Tyr Arg Lys His Thr Gly Gln
325 330 335
Arg Pro Phe Arg Cys Gln Leu Cys Pro Arg Ala Phe Ser Arg Ser Asp
340 345 350
His Leu Ala Leu His Met Lys Arg His Leu
355 360
<210> 44
<211> 319
<212> PRT
<213> 人类
<400> 44
Met Glu Leu Leu Ser Pro Pro Leu Arg Asp Val Asp Leu Thr Ala Pro
1 5 10 15
Asp Gly Ser Leu Cys Ser Phe Ala Thr Thr Asp Asp Phe Tyr Asp Asp
20 25 30
Pro Cys Phe Asp Ser Pro Asp Leu Arg Phe Phe Glu Asp Leu Asp Pro
35 40 45
Arg Leu Met His Val Gly Ala Leu Leu Lys Pro Glu Glu His Ser His
50 55 60
Phe Pro Ala Ala Val His Pro Ala Pro Gly Ala Arg Glu Asp Glu His
65 70 75 80
Val Arg Ala Pro Ser Gly His His Gln Ala Gly Arg Cys Leu Leu Trp
85 90 95
Ala Cys Lys Ala Cys Lys Arg Lys Thr Thr Asn Ala Asp Arg Arg Lys
100 105 110
Ala Ala Thr Met Arg Glu Arg Arg Arg Leu Ser Lys Val Asn Glu Ala
115 120 125
Phe Glu Thr Leu Lys Arg Cys Thr Ser Ser Asn Pro Asn Gln Arg Leu
130 135 140
Pro Lys Val Glu Ile Leu Arg Asn Ala Ile Arg Tyr Ile Glu Gly Leu
145 150 155 160
Gln Ala Leu Leu Arg Asp Gln Asp Ala Ala Pro Pro Gly Ala Ala Ala
165 170 175
Phe Tyr Ala Pro Gly Pro Leu Pro Pro Gly Arg Gly Gly Glu His Tyr
180 185 190
Ser Gly Asp Ser Asp Ala Ser Ser Pro Arg Ser Asn Cys Ser Asp Gly
195 200 205
Met Met Asp Tyr Ser Gly Pro Pro Ser Gly Ala Arg Arg Arg Asn Cys
210 215 220
Tyr Glu Gly Ala Tyr Tyr Asn Glu Ala Pro Ser Glu Pro Arg Pro Gly
225 230 235 240
Lys Ser Ala Ala Val Ser Ser Leu Asp Tyr Leu Ser Ser Ile Val Glu
245 250 255
Arg Ile Ser Thr Glu Ser Pro Ala Ala Pro Ala Leu Leu Leu Ala Asp
260 265 270
Val Pro Ser Glu Ser Pro Pro Arg Arg Gln Glu Ala Ala Ala Pro Ser
275 280 285
Glu Gly Glu Ser Ser Gly Asp Pro Thr Gln Ser Pro Asp Ala Ala Pro
290 295 300
Gln Cys Pro Ala Gly Ala Asn Pro Asn Pro Ile Tyr Gln Val Leu
305 310 315
<210> 45
<211> 525
<212> PRT
<213> 人类
<400> 45
Met His Arg Ala Pro Ser Pro Thr Ala Glu Gln Pro Pro Gly Gly Gly
1 5 10 15
Asp Ser Ala Arg Arg Thr Leu Gln Pro Arg Leu Lys Pro Ser Ala Arg
20 25 30
Ala Met Ala Leu Pro Arg Thr Leu Gly Glu Leu Gln Leu Tyr Arg Val
35 40 45
Leu Gln Arg Ala Asn Leu Leu Ser Tyr Tyr Glu Thr Phe Ile Gln Gln
50 55 60
Gly Gly Asp Asp Val Gln Gln Leu Cys Glu Ala Gly Glu Glu Glu Phe
65 70 75 80
Leu Glu Ile Met Ala Leu Val Gly Met Ala Thr Lys Pro Leu His Val
85 90 95
Arg Arg Leu Gln Lys Ala Leu Arg Glu Trp Ala Thr Asn Pro Gly Leu
100 105 110
Phe Ser Gln Pro Val Pro Ala Val Pro Val Ser Ser Ile Pro Leu Phe
115 120 125
Lys Ile Ser Glu Thr Ala Gly Thr Arg Lys Gly Ser Met Ser Asn Gly
130 135 140
His Gly Ser Pro Gly Glu Lys Ala Gly Ser Ala Arg Ser Phe Ser Pro
145 150 155 160
Lys Ser Pro Leu Glu Leu Gly Glu Lys Leu Ser Pro Leu Pro Gly Gly
165 170 175
Pro Gly Ala Gly Asp Pro Arg Ile Trp Pro Gly Arg Ser Thr Pro Glu
180 185 190
Ser Asp Val Gly Ala Gly Gly Glu Glu Glu Ala Gly Ser Pro Pro Phe
195 200 205
Ser Pro Pro Ala Gly Gly Gly Val Pro Glu Gly Thr Gly Ala Gly Gly
210 215 220
Leu Ala Ala Gly Gly Thr Gly Gly Gly Pro Asp Arg Leu Glu Pro Glu
225 230 235 240
Met Val Arg Met Val Val Glu Ser Val Glu Arg Ile Phe Arg Ser Phe
245 250 255
Pro Arg Gly Asp Ala Gly Glu Val Thr Ser Leu Leu Lys Leu Asn Lys
260 265 270
Lys Leu Ala Arg Ser Val Gly His Ile Phe Glu Met Asp Asp Asn Asp
275 280 285
Ser Gln Lys Glu Glu Glu Ile Arg Lys Tyr Ser Ile Ile Tyr Gly Arg
290 295 300
Phe Asp Ser Lys Arg Arg Glu Gly Lys Gln Leu Ser Leu His Glu Leu
305 310 315 320
Thr Ile Asn Glu Ala Ala Ala Gln Phe Cys Met Arg Asp Asn Thr Leu
325 330 335
Leu Leu Arg Arg Val Glu Leu Phe Ser Leu Ser Arg Gln Val Ala Arg
340 345 350
Glu Ser Thr Tyr Leu Ser Ser Leu Lys Gly Ser Arg Leu His Pro Glu
355 360 365
Glu Leu Gly Gly Pro Pro Leu Lys Lys Leu Lys Gln Glu Val Gly Glu
370 375 380
Gln Ser His Pro Glu Ile Gln Gln Pro Pro Pro Gly Pro Glu Ser Tyr
385 390 395 400
Val Pro Pro Tyr Arg Pro Ser Leu Glu Glu Asp Ser Ala Ser Leu Ser
405 410 415
Gly Glu Ser Leu Asp Gly His Leu Gln Ala Val Gly Ser Cys Pro Arg
420 425 430
Leu Thr Pro Pro Pro Ala Asp Leu Pro Leu Ala Leu Pro Ala His Gly
435 440 445
Leu Trp Ser Arg His Ile Leu Gln Gln Thr Leu Met Asp Glu Gly Leu
450 455 460
Arg Leu Ala Arg Leu Val Ser His Asp Arg Val Gly Arg Leu Ser Pro
465 470 475 480
Cys Val Pro Ala Lys Pro Pro Leu Ala Glu Phe Glu Glu Gly Leu Leu
485 490 495
Asp Arg Cys Pro Ala Pro Gly Pro His Pro Ala Leu Val Glu Gly Arg
500 505 510
Arg Ser Ser Val Lys Val Glu Ala Glu Ala Ser Arg Gln
515 520 525
<210> 46
<211> 543
<212> PRT
<213> 人类
<400> 46
Met Ala Ala Ala Lys Ala Glu Met Gln Leu Met Ser Pro Leu Gln Ile
1 5 10 15
Ser Asp Pro Phe Gly Ser Phe Pro His Ser Pro Thr Met Asp Asn Tyr
20 25 30
Pro Lys Leu Glu Glu Met Met Leu Leu Ser Asn Gly Ala Pro Gln Phe
35 40 45
Leu Gly Ala Ala Gly Ala Pro Glu Gly Ser Gly Ser Asn Ser Ser Ser
50 55 60
Ser Ser Ser Gly Gly Gly Gly Gly Gly Gly Gly Gly Ser Asn Ser Ser
65 70 75 80
Ser Ser Ser Ser Thr Phe Asn Pro Gln Ala Asp Thr Gly Glu Gln Pro
85 90 95
Tyr Glu His Leu Thr Ala Glu Ser Phe Pro Asp Ile Ser Leu Asn Asn
100 105 110
Glu Lys Val Leu Val Glu Thr Ser Tyr Pro Ser Gln Thr Thr Arg Leu
115 120 125
Pro Pro Ile Thr Tyr Thr Gly Arg Phe Ser Leu Glu Pro Ala Pro Asn
130 135 140
Ser Gly Asn Thr Leu Trp Pro Glu Pro Leu Phe Ser Leu Val Ser Gly
145 150 155 160
Leu Val Ser Met Thr Asn Pro Pro Ala Ser Ser Ser Ser Ala Pro Ser
165 170 175
Pro Ala Ala Ser Ser Ala Ser Ala Ser Gln Ser Pro Pro Leu Ser Cys
180 185 190
Ala Val Pro Ser Asn Asp Ser Ser Pro Ile Tyr Ser Ala Ala Pro Thr
195 200 205
Phe Pro Thr Pro Asn Thr Asp Ile Phe Pro Glu Pro Gln Ser Gln Ala
210 215 220
Phe Pro Gly Ser Ala Gly Thr Ala Leu Gln Tyr Pro Pro Pro Ala Tyr
225 230 235 240
Pro Ala Ala Lys Gly Gly Phe Gln Val Pro Met Ile Pro Asp Tyr Leu
245 250 255
Phe Pro Gln Gln Gln Gly Asp Leu Gly Leu Gly Thr Pro Asp Gln Lys
260 265 270
Pro Phe Gln Gly Leu Glu Ser Arg Thr Gln Gln Pro Ser Leu Thr Pro
275 280 285
Leu Ser Thr Ile Lys Ala Phe Ala Thr Gln Ser Gly Ser Gln Asp Leu
290 295 300
Lys Ala Leu Asn Thr Ser Tyr Gln Ser Gln Leu Ile Lys Pro Ser Arg
305 310 315 320
Met Arg Lys Tyr Pro Asn Arg Pro Ser Lys Thr Pro Pro His Glu Arg
325 330 335
Pro Tyr Ala Cys Pro Val Glu Ser Cys Asp Arg Arg Phe Ser Arg Ser
340 345 350
Asp Glu Leu Thr Arg His Ile Arg Ile His Thr Gly Gln Lys Pro Phe
355 360 365
Gln Cys Arg Ile Cys Met Arg Asn Phe Ser Arg Ser Asp His Leu Thr
370 375 380
Thr His Ile Arg Thr His Thr Gly Glu Lys Pro Phe Ala Cys Asp Ile
385 390 395 400
Cys Gly Arg Lys Phe Ala Arg Ser Asp Glu Arg Lys Arg His Thr Lys
405 410 415
Ile His Leu Arg Gln Lys Asp Lys Lys Ala Asp Lys Ser Val Val Ala
420 425 430
Ser Ser Ala Thr Ser Ser Leu Ser Ser Tyr Pro Ser Pro Val Ala Thr
435 440 445
Ser Tyr Pro Ser Pro Val Thr Thr Ser Tyr Pro Ser Pro Ala Thr Thr
450 455 460
Ser Tyr Pro Ser Pro Val Pro Thr Ser Phe Ser Ser Pro Gly Ser Ser
465 470 475 480
Thr Tyr Pro Ser Pro Val His Ser Gly Phe Pro Ser Pro Ser Val Ala
485 490 495
Thr Thr Tyr Ser Ser Val Pro Pro Ala Phe Pro Ala Gln Val Ser Ser
500 505 510
Phe Pro Ser Ser Ala Val Thr Asn Ser Phe Ser Ala Ser Thr Gly Leu
515 520 525
Ser Asp Met Thr Ala Thr Phe Ser Pro Arg Thr Ile Glu Ile Cys
530 535 540
<210> 47
<211> 422
<212> PRT
<213> 人类
<400> 47
Met Pro Arg Ser Phe Leu Val Lys Ser Lys Lys Ala His Ser Tyr His
1 5 10 15
Gln Pro Arg Ser Pro Gly Pro Asp Tyr Ser Leu Arg Leu Glu Asn Val
20 25 30
Pro Ala Pro Ser Arg Ala Asp Ser Thr Ser Asn Ala Gly Gly Ala Lys
35 40 45
Ala Glu Pro Arg Asp Arg Leu Ser Pro Glu Ser Gln Leu Thr Glu Ala
50 55 60
Pro Asp Arg Ala Ser Ala Ser Pro Asp Ser Cys Glu Gly Ser Val Cys
65 70 75 80
Glu Arg Ser Ser Glu Phe Glu Asp Phe Trp Arg Pro Pro Ser Pro Ser
85 90 95
Ala Ser Pro Ala Ser Glu Lys Ser Met Cys Pro Ser Leu Asp Glu Ala
100 105 110
Gln Pro Phe Pro Leu Pro Phe Lys Pro Tyr Ser Trp Ser Gly Leu Ala
115 120 125
Gly Ser Asp Leu Arg His Leu Val Gln Ser Tyr Arg Pro Cys Gly Ala
130 135 140
Leu Glu Arg Gly Ala Gly Leu Gly Leu Phe Cys Glu Pro Ala Pro Glu
145 150 155 160
Pro Gly His Pro Ala Ala Leu Tyr Gly Pro Lys Arg Ala Ala Gly Gly
165 170 175
Ala Gly Ala Gly Ala Pro Gly Ser Cys Ser Ala Gly Ala Gly Ala Thr
180 185 190
Ala Gly Pro Gly Leu Gly Leu Tyr Gly Asp Phe Gly Ser Ala Ala Ala
195 200 205
Gly Leu Tyr Glu Arg Pro Thr Ala Ala Ala Gly Leu Leu Tyr Pro Glu
210 215 220
Arg Gly His Gly Leu His Ala Asp Lys Gly Ala Gly Val Lys Val Glu
225 230 235 240
Ser Glu Leu Leu Cys Thr Arg Leu Leu Leu Gly Gly Gly Ser Tyr Lys
245 250 255
Cys Ile Lys Cys Ser Lys Val Phe Ser Thr Pro His Gly Leu Glu Val
260 265 270
His Val Arg Arg Ser His Ser Gly Thr Arg Pro Phe Ala Cys Glu Met
275 280 285
Cys Gly Lys Thr Phe Gly His Ala Val Ser Leu Glu Gln His Lys Ala
290 295 300
Val His Ser Gln Glu Arg Ser Phe Asp Cys Lys Ile Cys Gly Lys Ser
305 310 315 320
Phe Lys Arg Ser Ser Thr Leu Ser Thr His Leu Leu Ile His Ser Asp
325 330 335
Thr Arg Pro Tyr Pro Cys Gln Tyr Cys Gly Lys Arg Phe His Gln Lys
340 345 350
Ser Asp Met Lys Lys His Thr Phe Ile His Thr Gly Glu Lys Pro His
355 360 365
Lys Cys Gln Val Cys Gly Lys Ala Phe Ser Gln Ser Ser Asn Leu Ile
370 375 380
Thr His Ser Arg Lys His Thr Gly Phe Lys Pro Phe Gly Cys Asp Leu
385 390 395 400
Cys Gly Lys Gly Phe Gln Arg Lys Val Asp Leu Arg Arg His Arg Glu
405 410 415
Thr Gln His Gly Leu Lys
420
<210> 48
<211> 391
<212> PRT
<213> 人类
<400> 48
Met Asp Leu Glu Lys Asn Tyr Pro Thr Pro Arg Thr Ser Arg Thr Gly
1 5 10 15
His Gly Gly Val Asn Gln Leu Gly Gly Val Phe Val Asn Gly Arg Pro
20 25 30
Leu Pro Asp Val Val Arg Gln Arg Ile Val Glu Leu Ala His Gln Gly
35 40 45
Val Arg Pro Cys Asp Ile Ser Arg Gln Leu Arg Val Ser His Gly Cys
50 55 60
Val Ser Lys Ile Leu Gly Arg Tyr Tyr Glu Thr Gly Ser Ile Lys Pro
65 70 75 80
Gly Val Ile Gly Gly Ser Lys Pro Lys Val Ala Thr Pro Lys Val Val
85 90 95
Glu Lys Ile Ala Glu Tyr Lys Arg Gln Asn Pro Thr Met Phe Ala Trp
100 105 110
Glu Ile Arg Asp Arg Leu Leu Ala Glu Arg Val Cys Asp Asn Asp Thr
115 120 125
Val Pro Ser Val Ser Ser Ile Asn Arg Ile Ile Arg Thr Lys Val Gln
130 135 140
Gln Pro Pro Asn Gln Pro Val Pro Ala Ser Ser His Ser Ile Val Ser
145 150 155 160
Thr Gly Ser Val Thr Gln Val Ser Ser Val Ser Thr Asp Ser Ala Gly
165 170 175
Ser Ser Tyr Ser Ile Ser Gly Ile Leu Gly Ile Thr Ser Pro Ser Ala
180 185 190
Asp Thr Asn Lys Arg Lys Arg Asp Glu Gly Ile Gln Glu Ser Pro Val
195 200 205
Pro Asn Gly His Ser Leu Pro Gly Arg Asp Phe Leu Arg Lys Gln Met
210 215 220
Arg Gly Asp Leu Phe Thr Gln Gln Gln Leu Glu Val Leu Asp Arg Val
225 230 235 240
Phe Glu Arg Gln His Tyr Ser Asp Ile Phe Thr Thr Thr Glu Pro Ile
245 250 255
Lys Pro Glu Gln Thr Thr Glu Tyr Ser Ala Met Ala Ser Leu Ala Gly
260 265 270
Gly Leu Asp Asp Met Lys Ala Asn Leu Ala Ser Pro Thr Pro Ala Asp
275 280 285
Ile Gly Ser Ser Val Pro Gly Pro Gln Ser Tyr Pro Ile Val Thr Gly
290 295 300
Arg Asp Leu Ala Ser Thr Thr Leu Pro Gly Tyr Pro Pro His Val Pro
305 310 315 320
Pro Ala Gly Gln Gly Ser Tyr Ser Ala Pro Thr Leu Thr Gly Met Val
325 330 335
Pro Gly Ser Glu Phe Ser Gly Ser Pro Tyr Ser His Pro Gln Tyr Ser
340 345 350
Ser Tyr Asn Asp Ser Trp Arg Phe Pro Asn Pro Gly Leu Leu Gly Ser
355 360 365
Pro Tyr Tyr Tyr Ser Ala Ala Ala Arg Gly Ala Ala Pro Pro Ala Ala
370 375 380
Ala Thr Ala Tyr Asp Arg His
385 390
<210> 49
<211> 535
<212> PRT
<213> 人类
<400> 49
Met Gly Ile Val Glu Pro Gly Cys Gly Asp Met Leu Thr Gly Thr Glu
1 5 10 15
Pro Met Pro Gly Ser Asp Glu Gly Arg Ala Pro Gly Ala Asp Pro Gln
20 25 30
His Arg Tyr Phe Tyr Pro Glu Pro Gly Ala Gln Asp Ala Asp Glu Arg
35 40 45
Arg Gly Gly Gly Ser Leu Gly Ser Pro Tyr Pro Gly Gly Ala Leu Val
50 55 60
Pro Ala Pro Pro Ser Arg Phe Leu Gly Ala Tyr Ala Tyr Pro Pro Arg
65 70 75 80
Pro Gln Ala Ala Gly Phe Pro Gly Ala Gly Glu Ser Phe Pro Pro Pro
85 90 95
Ala Asp Ala Glu Gly Tyr Gln Pro Gly Glu Gly Tyr Ala Ala Pro Asp
100 105 110
Pro Arg Ala Gly Leu Tyr Pro Gly Pro Arg Glu Asp Tyr Ala Leu Pro
115 120 125
Ala Gly Leu Glu Val Ser Gly Lys Leu Arg Val Ala Leu Asn Asn His
130 135 140
Leu Leu Trp Ser Lys Phe Asn Gln His Gln Thr Glu Met Ile Ile Thr
145 150 155 160
Lys Gln Gly Arg Arg Met Phe Pro Phe Leu Ser Phe Thr Val Ala Gly
165 170 175
Leu Glu Pro Thr Ser His Tyr Arg Met Phe Val Asp Val Val Leu Val
180 185 190
Asp Gln His His Trp Arg Tyr Gln Ser Gly Lys Trp Val Gln Cys Gly
195 200 205
Lys Ala Glu Gly Ser Met Pro Gly Asn Arg Leu Tyr Val His Pro Asp
210 215 220
Ser Pro Asn Thr Gly Ala His Trp Met Arg Gln Glu Val Ser Phe Gly
225 230 235 240
Lys Leu Lys Leu Thr Asn Asn Lys Gly Ala Ser Asn Asn Val Thr Gln
245 250 255
Met Ile Val Leu Gln Ser Leu His Lys Tyr Gln Pro Arg Leu His Ile
260 265 270
Val Glu Val Asn Asp Gly Glu Pro Glu Ala Ala Cys Asn Ala Ser Asn
275 280 285
Thr His Ile Phe Thr Phe Gln Glu Thr Gln Phe Ile Ala Val Thr Ala
290 295 300
Tyr Gln Asn Ala Glu Ile Thr Gln Leu Lys Ile Asp Asn Asn Pro Phe
305 310 315 320
Ala Lys Gly Phe Arg Glu Asn Phe Glu Ser Met Tyr Thr Ser Val Asp
325 330 335
Thr Ser Ile Pro Ser Pro Pro Gly Pro Asn Cys Gln Phe Leu Gly Gly
340 345 350
Asp His Tyr Ser Pro Leu Leu Pro Asn Gln Tyr Pro Val Pro Ser Arg
355 360 365
Phe Tyr Pro Asp Leu Pro Gly Gln Ala Lys Asp Val Val Pro Gln Ala
370 375 380
Tyr Trp Leu Gly Ala Pro Arg Asp His Ser Tyr Glu Ala Glu Phe Arg
385 390 395 400
Ala Val Ser Met Lys Pro Ala Phe Leu Pro Ser Ala Pro Gly Pro Thr
405 410 415
Met Ser Tyr Tyr Arg Gly Gln Glu Val Leu Ala Pro Gly Ala Gly Trp
420 425 430
Pro Val Ala Pro Gln Tyr Pro Pro Lys Met Gly Pro Ala Ser Trp Phe
435 440 445
Arg Pro Met Arg Thr Leu Pro Met Glu Pro Gly Pro Gly Gly Ser Glu
450 455 460
Gly Arg Gly Pro Glu Asp Gln Gly Pro Pro Leu Val Trp Thr Glu Ile
465 470 475 480
Ala Pro Ile Arg Pro Glu Ser Ser Asp Ser Gly Leu Gly Glu Gly Asp
485 490 495
Ser Lys Arg Arg Arg Val Ser Pro Tyr Pro Ser Ser Gly Asp Ser Ser
500 505 510
Ser Pro Ala Gly Ala Pro Ser Pro Phe Asp Lys Glu Ala Glu Gly Gln
515 520 525
Phe Tyr Asn Tyr Phe Pro Asn
530 535
<210> 50
<211> 444
<212> PRT
<213> 人类
<400> 50
Met Glu Val Thr Ala Asp Gln Pro Arg Trp Val Ser His His His Pro
1 5 10 15
Ala Val Leu Asn Gly Gln His Pro Asp Thr His His Pro Gly Leu Ser
20 25 30
His Ser Tyr Met Asp Ala Ala Gln Tyr Pro Leu Pro Glu Glu Val Asp
35 40 45
Val Leu Phe Asn Ile Asp Gly Gln Gly Asn His Val Pro Pro Tyr Tyr
50 55 60
Gly Asn Ser Val Arg Ala Thr Val Gln Arg Tyr Pro Pro Thr His His
65 70 75 80
Gly Ser Gln Val Cys Arg Pro Pro Leu Leu His Gly Ser Leu Pro Trp
85 90 95
Leu Asp Gly Gly Lys Ala Leu Gly Ser His His Thr Ala Ser Pro Trp
100 105 110
Asn Leu Ser Pro Phe Ser Lys Thr Ser Ile His His Gly Ser Pro Gly
115 120 125
Pro Leu Ser Val Tyr Pro Pro Ala Ser Ser Ser Ser Leu Ser Gly Gly
130 135 140
His Ala Ser Pro His Leu Phe Thr Phe Pro Pro Thr Pro Pro Lys Asp
145 150 155 160
Val Ser Pro Asp Pro Ser Leu Ser Thr Pro Gly Ser Ala Gly Ser Ala
165 170 175
Arg Gln Asp Glu Lys Glu Cys Leu Lys Tyr Gln Val Pro Leu Pro Asp
180 185 190
Ser Met Lys Leu Glu Ser Ser His Ser Arg Gly Ser Met Thr Ala Leu
195 200 205
Gly Gly Ala Ser Ser Ser Thr His His Pro Ile Thr Thr Tyr Pro Pro
210 215 220
Tyr Val Pro Glu Tyr Ser Ser Gly Leu Phe Pro Pro Ser Ser Leu Leu
225 230 235 240
Gly Gly Ser Pro Thr Gly Phe Gly Cys Lys Ser Arg Pro Lys Ala Arg
245 250 255
Ser Ser Thr Glu Gly Arg Glu Cys Val Asn Cys Gly Ala Thr Ser Thr
260 265 270
Pro Leu Trp Arg Arg Asp Gly Thr Gly His Tyr Leu Cys Asn Ala Cys
275 280 285
Gly Leu Tyr His Lys Met Asn Gly Gln Asn Arg Pro Leu Ile Lys Pro
290 295 300
Lys Arg Arg Leu Ser Ala Ala Arg Arg Ala Gly Thr Ser Cys Ala Asn
305 310 315 320
Cys Gln Thr Thr Thr Thr Thr Leu Trp Arg Arg Asn Ala Asn Gly Asp
325 330 335
Pro Val Cys Asn Ala Cys Gly Leu Tyr Tyr Lys Leu His Asn Ile Asn
340 345 350
Arg Pro Leu Thr Met Lys Lys Glu Gly Ile Gln Thr Arg Asn Arg Lys
355 360 365
Met Ser Ser Lys Ser Lys Lys Cys Lys Lys Val His Asp Ser Leu Glu
370 375 380
Asp Phe Pro Lys Asn Ser Ser Phe Asn Pro Ala Ala Leu Ser Arg His
385 390 395 400
Met Ser Ser Leu Ser His Ile Ser Pro Phe Ser His Ser Ser His Met
405 410 415
Leu Thr Thr Pro Thr Pro Met His Pro Pro Ser Ser Leu Ser Phe Gly
420 425 430
Pro His His Pro Ser Ser Met Val Thr Ala Met Gly
435 440
<210> 51
<211> 431
<212> PRT
<213> 人类
<400> 51
Met Pro Asn Pro Arg Pro Gly Lys Pro Ser Ala Pro Ser Leu Ala Leu
1 5 10 15
Gly Pro Ser Pro Gly Ala Ser Pro Ser Trp Arg Ala Ala Pro Lys Ala
20 25 30
Ser Asp Leu Leu Gly Ala Arg Gly Pro Gly Gly Thr Phe Gln Gly Arg
35 40 45
Asp Leu Arg Gly Gly Ala His Ala Ser Ser Ser Ser Leu Asn Pro Met
50 55 60
Pro Pro Ser Gln Leu Gln Leu Pro Thr Leu Pro Leu Val Met Val Ala
65 70 75 80
Pro Ser Gly Ala Arg Leu Gly Pro Leu Pro His Leu Gln Ala Leu Leu
85 90 95
Gln Asp Arg Pro His Phe Met His Gln Leu Ser Thr Val Asp Ala His
100 105 110
Ala Arg Thr Pro Val Leu Gln Val His Pro Leu Glu Ser Pro Ala Met
115 120 125
Ile Ser Leu Thr Pro Pro Thr Thr Ala Thr Gly Val Phe Ser Leu Lys
130 135 140
Ala Arg Pro Gly Leu Pro Pro Gly Ile Asn Val Ala Ser Leu Glu Trp
145 150 155 160
Val Ser Arg Glu Pro Ala Leu Leu Cys Thr Phe Pro Asn Pro Ser Ala
165 170 175
Pro Arg Lys Asp Ser Thr Leu Ser Ala Val Pro Gln Ser Ser Tyr Pro
180 185 190
Leu Leu Ala Asn Gly Val Cys Lys Trp Pro Gly Cys Glu Lys Val Phe
195 200 205
Glu Glu Pro Glu Asp Phe Leu Lys His Cys Gln Ala Asp His Leu Leu
210 215 220
Asp Glu Lys Gly Arg Ala Gln Cys Leu Leu Gln Arg Glu Met Val Gln
225 230 235 240
Ser Leu Glu Gln Gln Leu Val Leu Glu Lys Glu Lys Leu Ser Ala Met
245 250 255
Gln Ala His Leu Ala Gly Lys Met Ala Leu Thr Lys Ala Ser Ser Val
260 265 270
Ala Ser Ser Asp Lys Gly Ser Cys Cys Ile Val Ala Ala Gly Ser Gln
275 280 285
Gly Pro Val Val Pro Ala Trp Ser Gly Pro Arg Glu Ala Pro Asp Ser
290 295 300
Leu Phe Ala Val Arg Arg His Leu Trp Gly Ser His Gly Asn Ser Thr
305 310 315 320
Phe Pro Glu Phe Leu His Asn Met Asp Tyr Phe Lys Phe His Asn Met
325 330 335
Arg Pro Pro Phe Thr Tyr Ala Thr Leu Ile Arg Trp Ala Ile Leu Glu
340 345 350
Ala Pro Glu Lys Gln Arg Thr Leu Asn Glu Ile Tyr His Trp Phe Thr
355 360 365
Arg Met Phe Ala Phe Phe Arg Asn His Pro Ala Thr Trp Lys Asn Ala
370 375 380
Ile Arg His Asn Leu Ser Leu His Lys Cys Phe Val Arg Val Glu Ser
385 390 395 400
Glu Lys Gly Ala Val Trp Thr Val Asp Glu Leu Glu Phe Arg Lys Lys
405 410 415
Arg Ser Gln Arg Pro Ser Arg Cys Ser Asn Pro Thr Pro Gly Pro
420 425 430
<210> 52
<211> 560
<212> PRT
<213> 人类
<400> 52
Met Asp Arg Ala Pro Gln Arg Gln His Arg Ala Ser Arg Glu Leu Leu
1 5 10 15
Ala Ala Lys Lys Thr His Thr Ser Gln Ile Glu Val Ile Pro Cys Lys
20 25 30
Ile Cys Gly Asp Lys Ser Ser Gly Ile His Tyr Gly Val Ile Thr Cys
35 40 45
Glu Gly Cys Lys Gly Phe Phe Arg Arg Ser Gln Arg Cys Asn Ala Ala
50 55 60
Tyr Ser Cys Thr Arg Gln Gln Asn Cys Pro Ile Asp Arg Thr Ser Arg
65 70 75 80
Asn Arg Cys Gln His Cys Arg Leu Gln Lys Cys Leu Ala Leu Gly Met
85 90 95
Ser Arg Asp Ala Val Lys Phe Gly Arg Met Ser Lys Lys Gln Arg Asp
100 105 110
Ser Leu His Ala Glu Val Gln Lys Gln Leu Gln Gln Arg Gln Gln Gln
115 120 125
Gln Gln Glu Pro Val Val Lys Thr Pro Pro Ala Gly Ala Gln Gly Ala
130 135 140
Asp Thr Leu Thr Tyr Thr Leu Gly Leu Pro Asp Gly Gln Leu Pro Leu
145 150 155 160
Gly Ser Ser Pro Asp Leu Pro Glu Ala Ser Ala Cys Pro Pro Gly Leu
165 170 175
Leu Lys Ala Ser Gly Ser Gly Pro Ser Tyr Ser Asn Asn Leu Ala Lys
180 185 190
Ala Gly Leu Asn Gly Ala Ser Cys His Leu Glu Tyr Ser Pro Glu Arg
195 200 205
Gly Lys Ala Glu Gly Arg Glu Ser Phe Tyr Ser Thr Gly Ser Gln Leu
210 215 220
Thr Pro Asp Arg Cys Gly Leu Arg Phe Glu Glu His Arg His Pro Gly
225 230 235 240
Leu Gly Glu Leu Gly Gln Gly Pro Asp Ser Tyr Gly Ser Pro Ser Phe
245 250 255
Arg Ser Thr Pro Glu Ala Pro Tyr Ala Ser Leu Thr Glu Ile Glu His
260 265 270
Leu Val Gln Ser Val Cys Lys Ser Tyr Arg Glu Thr Cys Gln Leu Arg
275 280 285
Leu Glu Asp Leu Leu Arg Gln Arg Ser Asn Ile Phe Ser Arg Glu Glu
290 295 300
Val Thr Gly Tyr Gln Arg Lys Ser Met Trp Glu Met Trp Glu Arg Cys
305 310 315 320
Ala His His Leu Thr Glu Ala Ile Gln Tyr Val Val Glu Phe Ala Lys
325 330 335
Arg Leu Ser Gly Phe Met Glu Leu Cys Gln Asn Asp Gln Ile Val Leu
340 345 350
Leu Lys Ala Gly Ala Met Glu Val Val Leu Val Arg Met Cys Arg Ala
355 360 365
Tyr Asn Ala Asp Asn Arg Thr Val Phe Phe Glu Gly Lys Tyr Gly Gly
370 375 380
Met Glu Leu Phe Arg Ala Leu Gly Cys Ser Glu Leu Ile Ser Ser Ile
385 390 395 400
Phe Asp Phe Ser His Ser Leu Ser Ala Leu His Phe Ser Glu Asp Glu
405 410 415
Ile Ala Leu Tyr Thr Ala Leu Val Leu Ile Asn Ala His Arg Pro Gly
420 425 430
Leu Gln Glu Lys Arg Lys Val Glu Gln Leu Gln Tyr Asn Leu Glu Leu
435 440 445
Ala Phe His His His Leu Cys Lys Thr His Arg Gln Ser Ile Leu Ala
450 455 460
Lys Leu Pro Pro Lys Gly Lys Leu Arg Ser Leu Cys Ser Gln His Val
465 470 475 480
Glu Arg Leu Gln Ile Phe Gln His Leu His Pro Ile Val Val Gln Ala
485 490 495
Ala Phe Pro Pro Leu Tyr Lys Glu Leu Phe Ser Thr Glu Thr Glu Ser
500 505 510
Pro Val Gly Cys Pro Ser Asp Leu Glu Glu Gly Leu Leu Ala Ser Pro
515 520 525
Tyr Gly Leu Leu Ala Thr Ser Leu Asp Pro Val Pro Pro Ser Pro Phe
530 535 540
Ser Phe Pro Met Asn Pro Gly Gly Trp Ser Pro Pro Ala Leu Trp Lys
545 550 555 560
<210> 53
<211> 464
<212> PRT
<213> 人类
<400> 53
Met Arg Leu Ser Lys Thr Leu Val Asp Met Asp Met Ala Asp Tyr Ser
1 5 10 15
Ala Ala Leu Asp Pro Ala Tyr Thr Thr Leu Glu Phe Glu Asn Val Gln
20 25 30
Val Leu Thr Met Gly Asn Asp Thr Ser Pro Ser Glu Gly Thr Asn Leu
35 40 45
Asn Ala Pro Asn Ser Leu Gly Val Ser Ala Leu Cys Ala Ile Cys Gly
50 55 60
Asp Arg Ala Thr Gly Lys His Tyr Gly Ala Ser Ser Cys Asp Gly Cys
65 70 75 80
Lys Gly Phe Phe Arg Arg Ser Val Arg Lys Asn His Met Tyr Ser Cys
85 90 95
Arg Phe Ser Arg Gln Cys Val Val Asp Lys Asp Lys Arg Asn Gln Cys
100 105 110
Arg Tyr Cys Arg Leu Lys Lys Cys Phe Arg Ala Gly Met Lys Lys Glu
115 120 125
Ala Val Gln Asn Glu Arg Asp Arg Ile Ser Thr Arg Arg Ser Ser Tyr
130 135 140
Glu Asp Ser Ser Leu Pro Ser Ile Asn Ala Leu Leu Gln Ala Glu Val
145 150 155 160
Leu Ser Arg Gln Ile Thr Ser Pro Val Ser Gly Ile Asn Gly Asp Ile
165 170 175
Arg Ala Lys Lys Ile Ala Ser Ile Ala Asp Val Cys Glu Ser Met Lys
180 185 190
Glu Gln Leu Leu Val Leu Val Glu Trp Ala Lys Tyr Ile Pro Ala Phe
195 200 205
Cys Glu Leu Pro Leu Asp Asp Gln Val Ala Leu Leu Arg Ala His Ala
210 215 220
Gly Glu His Leu Leu Leu Gly Ala Thr Lys Arg Ser Met Val Phe Lys
225 230 235 240
Asp Val Leu Leu Leu Gly Asn Asp Tyr Ile Val Pro Arg His Cys Pro
245 250 255
Glu Leu Ala Glu Met Ser Arg Val Ser Ile Arg Ile Leu Asp Glu Leu
260 265 270
Val Leu Pro Phe Gln Glu Leu Gln Ile Asp Asp Asn Glu Tyr Ala Tyr
275 280 285
Leu Lys Ala Ile Ile Phe Phe Asp Pro Asp Ala Lys Gly Leu Ser Asp
290 295 300
Pro Gly Lys Ile Lys Arg Leu Arg Ser Gln Val Gln Val Ser Leu Glu
305 310 315 320
Asp Tyr Ile Asn Asp Arg Gln Tyr Asp Ser Arg Gly Arg Phe Gly Glu
325 330 335
Leu Leu Leu Leu Leu Pro Thr Leu Gln Ser Ile Thr Trp Gln Met Ile
340 345 350
Glu Gln Ile Gln Phe Ile Lys Leu Phe Gly Met Ala Lys Ile Asp Asn
355 360 365
Leu Leu Gln Glu Met Leu Leu Gly Gly Ser Pro Ser Asp Ala Pro His
370 375 380
Ala His His Pro Leu His Pro His Leu Met Gln Glu His Met Gly Thr
385 390 395 400
Asn Val Ile Val Ala Asn Thr Met Pro Thr His Leu Ser Asn Gly Gln
405 410 415
Met Ser Thr Pro Glu Thr Pro Gln Pro Ser Pro Pro Gly Gly Ser Gly
420 425 430
Ser Glu Pro Tyr Lys Leu Leu Pro Gly Ala Val Ala Thr Ile Val Lys
435 440 445
Pro Leu Ser Ala Ile Pro Gln Pro Thr Ile Thr Lys Gln Glu Val Ile
450 455 460
<210> 54
<211> 794
<212> PRT
<213> 人类
<400> 54
Met Ala Gly Trp Ile Gln Ala Gln Gln Leu Gln Gly Asp Ala Leu Arg
1 5 10 15
Gln Met Gln Val Leu Tyr Gly Gln His Phe Pro Ile Glu Val Arg His
20 25 30
Tyr Leu Ala Gln Trp Ile Glu Ser Gln Pro Trp Asp Ala Ile Asp Leu
35 40 45
Asp Asn Pro Gln Asp Arg Ala Gln Ala Thr Gln Leu Leu Glu Gly Leu
50 55 60
Val Gln Glu Leu Gln Lys Lys Ala Glu His Gln Val Gly Glu Asp Gly
65 70 75 80
Phe Leu Leu Lys Ile Lys Leu Arg His Tyr Ala Thr Gln Leu Gln Lys
85 90 95
Thr Tyr Asp Arg Cys Pro Leu Glu Leu Val Arg Cys Ile Arg His Ile
100 105 110
Leu Tyr Asn Glu Gln Arg Leu Val Arg Glu Ala Asn Asn Cys Ser Ser
115 120 125
Pro Ala Gly Ile Leu Val Asp Ala Met Ser Gln Lys His Leu Gln Ile
130 135 140
Asn Gln Thr Phe Glu Glu Leu Arg Leu Val Thr Gln Asp Thr Glu Asn
145 150 155 160
Glu Leu Lys Lys Leu Gln Gln Thr Gln Glu Tyr Phe Ile Ile Gln Tyr
165 170 175
Gln Glu Ser Leu Arg Ile Gln Ala Gln Phe Ala Gln Leu Ala Gln Leu
180 185 190
Ser Pro Gln Glu Arg Leu Ser Arg Glu Thr Ala Leu Gln Gln Lys Gln
195 200 205
Val Ser Leu Glu Ala Trp Leu Gln Arg Glu Ala Gln Thr Leu Gln Gln
210 215 220
Tyr Arg Val Glu Leu Ala Glu Lys His Gln Lys Thr Leu Gln Leu Leu
225 230 235 240
Arg Lys Gln Gln Thr Ile Ile Leu Asp Asp Glu Leu Ile Gln Trp Lys
245 250 255
Arg Arg Gln Gln Leu Ala Gly Asn Gly Gly Pro Pro Glu Gly Ser Leu
260 265 270
Asp Val Leu Gln Ser Trp Cys Glu Lys Leu Ala Glu Ile Ile Trp Gln
275 280 285
Asn Arg Gln Gln Ile Arg Arg Ala Glu His Leu Cys Gln Gln Leu Pro
290 295 300
Ile Pro Gly Pro Val Glu Glu Met Leu Ala Glu Val Asn Ala Thr Ile
305 310 315 320
Thr Asp Ile Ile Ser Ala Leu Val Thr Ser Thr Phe Ile Ile Glu Lys
325 330 335
Gln Pro Pro Gln Val Leu Lys Thr Gln Thr Lys Phe Ala Ala Thr Val
340 345 350
Arg Leu Leu Val Gly Gly Lys Leu Asn Val His Met Asn Pro Pro Gln
355 360 365
Val Lys Ala Thr Ile Ile Ser Glu Gln Gln Ala Lys Ser Leu Leu Lys
370 375 380
Asn Glu Asn Thr Arg Asn Glu Cys Ser Gly Glu Ile Leu Asn Asn Cys
385 390 395 400
Cys Val Met Glu Tyr His Gln Ala Thr Gly Thr Leu Ser Ala His Phe
405 410 415
Arg Asn Met Ser Leu Lys Arg Ile Lys Arg Ala Asp Arg Arg Gly Ala
420 425 430
Glu Ser Val Thr Glu Glu Lys Phe Thr Val Leu Phe Glu Ser Gln Phe
435 440 445
Ser Val Gly Ser Asn Glu Leu Val Phe Gln Val Lys Thr Leu Ser Leu
450 455 460
Pro Val Val Val Ile Val His Gly Ser Gln Asp His Asn Ala Thr Ala
465 470 475 480
Thr Val Leu Trp Asp Asn Ala Phe Ala Glu Pro Gly Arg Val Pro Phe
485 490 495
Ala Val Pro Asp Lys Val Leu Trp Pro Gln Leu Cys Glu Ala Leu Asn
500 505 510
Met Lys Phe Lys Ala Glu Val Gln Ser Asn Arg Gly Leu Thr Lys Glu
515 520 525
Asn Leu Val Phe Leu Ala Gln Lys Leu Phe Asn Asn Ser Ser Ser His
530 535 540
Leu Glu Asp Tyr Ser Gly Leu Ser Val Ser Trp Ser Gln Phe Asn Arg
545 550 555 560
Glu Asn Leu Pro Gly Trp Asn Tyr Thr Phe Trp Gln Trp Phe Asp Gly
565 570 575
Val Met Glu Val Leu Lys Lys His His Lys Pro His Trp Asn Asp Gly
580 585 590
Ala Ile Leu Gly Phe Val Asn Lys Gln Gln Ala His Asp Leu Leu Ile
595 600 605
Asn Lys Pro Asp Gly Thr Phe Leu Leu Arg Phe Ser Asp Ser Glu Ile
610 615 620
Gly Gly Ile Thr Ile Ala Trp Lys Phe Asp Ser Pro Glu Arg Asn Leu
625 630 635 640
Trp Asn Leu Lys Pro Phe Thr Thr Arg Asp Phe Ser Ile Arg Ser Leu
645 650 655
Ala Asp Arg Leu Gly Asp Leu Ser Tyr Leu Ile Tyr Val Phe Pro Asp
660 665 670
Arg Pro Lys Asp Glu Val Phe Ser Lys Tyr Tyr Thr Pro Val Leu Ala
675 680 685
Lys Ala Val Asp Gly Tyr Val Lys Pro Gln Ile Lys Gln Val Val Pro
690 695 700
Glu Phe Val Asn Ala Ser Ala Asp Ala Gly Gly Ser Ser Ala Thr Tyr
705 710 715 720
Met Asp Gln Ala Pro Ser Pro Ala Val Cys Pro Gln Ala Pro Tyr Asn
725 730 735
Met Tyr Pro Gln Asn Pro Asp His Val Leu Asp Gln Asp Gly Glu Phe
740 745 750
Asp Leu Asp Glu Thr Met Asp Val Ala Arg His Val Glu Glu Leu Leu
755 760 765
Arg Arg Pro Met Asp Ser Leu Asp Ser Arg Leu Ser Pro Pro Ala Gly
770 775 780
Leu Phe Thr Ser Ala Arg Gly Ser Leu Ser
785 790
<210> 55
<211> 574
<212> PRT
<213> 人类
<400> 55
Met Trp Thr Phe Leu Gly Ile Ala Thr Phe Thr Tyr Phe Tyr Lys Lys
1 5 10 15
Phe Gly Asp Phe Ile Thr Leu Ala Asn Arg Glu Val Leu Leu Cys Val
20 25 30
Leu Val Phe Leu Ser Leu Gly Leu Val Leu Ser Tyr Arg Cys Arg His
35 40 45
Arg Asn Gly Gly Leu Leu Gly Arg Gln Gln Ser Gly Ser Gln Phe Ala
50 55 60
Leu Phe Ser Asp Ile Leu Ser Gly Leu Pro Phe Ile Gly Phe Phe Trp
65 70 75 80
Ala Lys Ser Pro Pro Glu Ser Glu Asn Lys Glu Gln Leu Glu Ala Arg
85 90 95
Arg Arg Arg Lys Gly Thr Asn Ile Ser Glu Thr Ser Leu Ile Gly Thr
100 105 110
Ala Ala Cys Thr Ser Thr Ser Ser Gln Asn Asp Pro Glu Val Ile Ile
115 120 125
Val Gly Ala Gly Val Leu Gly Ser Ala Leu Ala Ala Val Leu Ser Arg
130 135 140
Asp Gly Arg Lys Val Thr Val Ile Glu Arg Asp Leu Lys Glu Pro Asp
145 150 155 160
Arg Ile Val Gly Glu Phe Leu Gln Pro Gly Gly Tyr His Val Leu Lys
165 170 175
Asp Leu Gly Leu Gly Asp Thr Val Glu Gly Leu Asp Ala Gln Val Val
180 185 190
Asn Gly Tyr Met Ile His Asp Gln Glu Ser Lys Ser Glu Val Gln Ile
195 200 205
Pro Tyr Pro Leu Ser Glu Asn Asn Gln Val Gln Ser Gly Arg Ala Phe
210 215 220
His His Gly Arg Phe Ile Met Ser Leu Arg Lys Ala Ala Met Ala Glu
225 230 235 240
Pro Asn Ala Lys Phe Ile Glu Gly Val Val Leu Gln Leu Leu Glu Glu
245 250 255
Asp Asp Val Val Met Gly Val Gln Tyr Lys Asp Lys Glu Thr Gly Asp
260 265 270
Ile Lys Glu Leu His Ala Pro Leu Thr Val Val Ala Asp Gly Leu Phe
275 280 285
Ser Lys Phe Arg Lys Ser Leu Val Ser Asn Lys Val Ser Val Ser Ser
290 295 300
His Phe Val Gly Phe Leu Met Lys Asn Ala Pro Gln Phe Lys Ala Asn
305 310 315 320
His Ala Glu Leu Ile Leu Ala Asn Pro Ser Pro Val Leu Ile Tyr Gln
325 330 335
Ile Ser Ser Ser Glu Thr Arg Val Leu Val Asp Ile Arg Gly Glu Met
340 345 350
Pro Arg Asn Leu Arg Glu Tyr Met Val Glu Lys Ile Tyr Pro Gln Ile
355 360 365
Pro Asp His Leu Lys Glu Pro Phe Leu Glu Ala Thr Asp Asn Ser His
370 375 380
Leu Arg Ser Met Pro Ala Ser Phe Leu Pro Pro Ser Ser Val Lys Lys
385 390 395 400
Arg Gly Val Leu Leu Leu Gly Asp Ala Tyr Asn Met Arg His Pro Leu
405 410 415
Thr Gly Gly Gly Met Thr Val Ala Phe Lys Asp Ile Lys Leu Trp Arg
420 425 430
Lys Leu Leu Lys Gly Ile Pro Asp Leu Tyr Asp Asp Ala Ala Ile Phe
435 440 445
Glu Ala Lys Lys Ser Phe Tyr Trp Ala Arg Lys Thr Ser His Ser Phe
450 455 460
Val Val Asn Ile Leu Ala Gln Ala Leu Tyr Glu Leu Phe Ser Ala Thr
465 470 475 480
Asp Asp Ser Leu His Gln Leu Arg Lys Ala Cys Phe Leu Tyr Phe Lys
485 490 495
Leu Gly Gly Glu Cys Val Ala Gly Pro Val Gly Leu Leu Ser Val Leu
500 505 510
Ser Pro Asn Pro Leu Val Leu Ile Gly His Phe Phe Ala Val Ala Ile
515 520 525
Tyr Ala Val Tyr Phe Cys Phe Lys Ser Glu Pro Trp Ile Thr Lys Pro
530 535 540
Arg Ala Leu Leu Ser Ser Gly Ala Val Leu Tyr Lys Ala Cys Ser Val
545 550 555 560
Ile Phe Pro Leu Ile Tyr Ser Glu Met Lys Tyr Met Val His
565 570
<210> 56
<211> 342
<212> PRT
<213> 人类
<400> 56
Met Asp Leu Trp Asn Trp Asp Glu Ala Ser Pro Gln Glu Val Pro Pro
1 5 10 15
Gly Asn Lys Leu Ala Gly Leu Glu Gly Ala Lys Leu Gly Phe Cys Phe
20 25 30
Pro Asp Leu Ala Leu Gln Gly Asp Thr Pro Thr Ala Thr Ala Glu Thr
35 40 45
Cys Trp Lys Gly Thr Ser Ser Ser Leu Ala Ser Phe Pro Gln Leu Asp
50 55 60
Trp Gly Ser Ala Leu Leu His Pro Glu Val Pro Trp Gly Ala Glu Pro
65 70 75 80
Asp Ser Gln Ala Leu Pro Trp Ser Gly Asp Trp Thr Asp Met Ala Cys
85 90 95
Thr Ala Trp Asp Ser Trp Ser Gly Ala Ser Gln Thr Leu Gly Pro Ala
100 105 110
Pro Leu Gly Pro Gly Pro Ile Pro Ala Ala Gly Ser Glu Gly Ala Ala
115 120 125
Gly Gln Asn Cys Val Pro Val Ala Gly Glu Ala Thr Ser Trp Ser Arg
130 135 140
Ala Gln Ala Ala Gly Ser Asn Thr Ser Trp Asp Cys Ser Val Gly Pro
145 150 155 160
Asp Gly Asp Thr Tyr Trp Gly Ser Gly Leu Gly Gly Glu Pro Arg Thr
165 170 175
Asp Cys Thr Ile Ser Trp Gly Gly Pro Ala Gly Pro Asp Cys Thr Thr
180 185 190
Ser Trp Asn Pro Gly Leu His Ala Gly Gly Thr Thr Ser Leu Lys Arg
195 200 205
Tyr Gln Ser Ser Ala Leu Thr Val Cys Ser Glu Pro Ser Pro Gln Ser
210 215 220
Asp Arg Ala Ser Leu Ala Arg Cys Pro Lys Thr Asn His Arg Gly Pro
225 230 235 240
Ile Gln Leu Trp Gln Phe Leu Leu Glu Leu Leu His Asp Gly Ala Arg
245 250 255
Ser Ser Cys Ile Arg Trp Thr Gly Asn Ser Arg Glu Phe Gln Leu Cys
260 265 270
Asp Pro Lys Glu Val Ala Arg Leu Trp Gly Glu Arg Lys Arg Lys Pro
275 280 285
Gly Met Asn Tyr Glu Lys Leu Ser Arg Gly Leu Arg Tyr Tyr Tyr Arg
290 295 300
Arg Asp Ile Val Arg Lys Ser Gly Gly Arg Lys Tyr Thr Tyr Arg Phe
305 310 315 320
Gly Gly Arg Val Pro Ser Leu Ala Tyr Pro Asp Cys Ala Gly Gly Gly
325 330 335
Arg Gly Ala Glu Thr Gln
340
<210> 57
<211> 480
<212> PRT
<213> 人类
<400> 57
Met Glu Val Ala Pro Glu Gln Pro Arg Trp Met Ala His Pro Ala Val
1 5 10 15
Leu Asn Ala Gln His Pro Asp Ser His His Pro Gly Leu Ala His Asn
20 25 30
Tyr Met Glu Pro Ala Gln Leu Leu Pro Pro Asp Glu Val Asp Val Phe
35 40 45
Phe Asn His Leu Asp Ser Gln Gly Asn Pro Tyr Tyr Ala Asn Pro Ala
50 55 60
His Ala Arg Ala Arg Val Ser Tyr Ser Pro Ala His Ala Arg Leu Thr
65 70 75 80
Gly Gly Gln Met Cys Arg Pro His Leu Leu His Ser Pro Gly Leu Pro
85 90 95
Trp Leu Asp Gly Gly Lys Ala Ala Leu Ser Ala Ala Ala Ala His His
100 105 110
His Asn Pro Trp Thr Val Ser Pro Phe Ser Lys Thr Pro Leu His Pro
115 120 125
Ser Ala Ala Gly Gly Pro Gly Gly Pro Leu Ser Val Tyr Pro Gly Ala
130 135 140
Gly Gly Gly Ser Gly Gly Gly Ser Gly Ser Ser Val Ala Ser Leu Thr
145 150 155 160
Pro Thr Ala Ala His Ser Gly Ser His Leu Phe Gly Phe Pro Pro Thr
165 170 175
Pro Pro Lys Glu Val Ser Pro Asp Pro Ser Thr Thr Gly Ala Ala Ser
180 185 190
Pro Ala Ser Ser Ser Ala Gly Gly Ser Ala Ala Arg Gly Glu Asp Lys
195 200 205
Asp Gly Val Lys Tyr Gln Val Ser Leu Thr Glu Ser Met Lys Met Glu
210 215 220
Ser Gly Ser Pro Leu Arg Pro Gly Leu Ala Thr Met Gly Thr Gln Pro
225 230 235 240
Ala Thr His His Pro Ile Pro Thr Tyr Pro Ser Tyr Val Pro Ala Ala
245 250 255
Ala His Asp Tyr Ser Ser Gly Leu Phe His Pro Gly Gly Phe Leu Gly
260 265 270
Gly Pro Ala Ser Ser Phe Thr Pro Lys Gln Arg Ser Lys Ala Arg Ser
275 280 285
Cys Ser Glu Gly Arg Glu Cys Val Asn Cys Gly Ala Thr Ala Thr Pro
290 295 300
Leu Trp Arg Arg Asp Gly Thr Gly His Tyr Leu Cys Asn Ala Cys Gly
305 310 315 320
Leu Tyr His Lys Met Asn Gly Gln Asn Arg Pro Leu Ile Lys Pro Lys
325 330 335
Arg Arg Leu Ser Ala Ala Arg Arg Ala Gly Thr Cys Cys Ala Asn Cys
340 345 350
Gln Thr Thr Thr Thr Thr Leu Trp Arg Arg Asn Ala Asn Gly Asp Pro
355 360 365
Val Cys Asn Ala Cys Gly Leu Tyr Tyr Lys Leu His Asn Val Asn Arg
370 375 380
Pro Leu Thr Met Lys Lys Glu Gly Ile Gln Thr Arg Asn Arg Lys Met
385 390 395 400
Ser Asn Lys Ser Lys Lys Ser Lys Lys Gly Ala Glu Cys Phe Glu Glu
405 410 415
Leu Ser Lys Cys Met Gln Glu Lys Ser Ser Pro Phe Ser Ala Ala Ala
420 425 430
Leu Ala Gly His Met Ala Pro Val Gly His Leu Pro Pro Phe Ser His
435 440 445
Ser Gly His Ile Leu Pro Thr Pro Thr Pro Ile His Pro Ser Ser Ser
450 455 460
Leu Ser Phe Gly His Pro His Pro Ser Ser Met Val Thr Ala Met Gly
465 470 475 480
<210> 58
<211> 304
<212> PRT
<213> 人类
<400> 58
Met Lys Arg Ala His Pro Glu Tyr Ser Ser Ser Asp Ser Glu Leu Asp
1 5 10 15
Glu Thr Ile Glu Val Glu Lys Glu Ser Ala Asp Glu Asn Gly Asn Leu
20 25 30
Ser Ser Ala Leu Gly Ser Met Ser Pro Thr Thr Ser Ser Gln Ile Leu
35 40 45
Ala Arg Lys Arg Arg Arg Gly Ile Ile Glu Lys Arg Arg Arg Asp Arg
50 55 60
Ile Asn Asn Ser Leu Ser Glu Leu Arg Arg Leu Val Pro Ser Ala Phe
65 70 75 80
Glu Lys Gln Gly Ser Ala Lys Leu Glu Lys Ala Glu Ile Leu Gln Met
85 90 95
Thr Val Asp His Leu Lys Met Leu His Thr Ala Gly Gly Lys Gly Tyr
100 105 110
Phe Asp Ala His Ala Leu Ala Met Asp Tyr Arg Ser Leu Gly Phe Arg
115 120 125
Glu Cys Leu Ala Glu Val Ala Arg Tyr Leu Ser Ile Ile Glu Gly Leu
130 135 140
Asp Ala Ser Asp Pro Leu Arg Val Arg Leu Val Ser His Leu Asn Asn
145 150 155 160
Tyr Ala Ser Gln Arg Glu Ala Ala Ser Gly Ala His Ala Gly Leu Gly
165 170 175
His Ile Pro Trp Gly Thr Val Phe Gly His His Pro His Ile Ala His
180 185 190
Pro Leu Leu Leu Pro Gln Asn Gly His Gly Asn Ala Gly Thr Thr Ala
195 200 205
Ser Pro Thr Glu Pro His His Gln Gly Arg Leu Gly Ser Ala His Pro
210 215 220
Glu Ala Pro Ala Leu Arg Ala Pro Pro Ser Gly Ser Leu Gly Pro Val
225 230 235 240
Leu Pro Val Val Thr Ser Ala Ser Lys Leu Ser Pro Pro Leu Leu Ser
245 250 255
Ser Val Ala Ser Leu Ser Ala Phe Pro Phe Ser Phe Gly Ser Phe His
260 265 270
Leu Leu Ser Pro Asn Ala Leu Ser Pro Ser Ala Pro Thr Gln Ala Ala
275 280 285
Asn Leu Gly Lys Pro Tyr Arg Pro Trp Gly Thr Glu Ile Gly Ala Phe
290 295 300
<210> 59
<211> 337
<212> PRT
<213> 人类
<400> 59
Met Lys Arg Pro Cys Glu Glu Thr Thr Ser Glu Ser Asp Met Asp Glu
1 5 10 15
Thr Ile Asp Val Gly Ser Glu Asn Asn Tyr Ser Gly Gln Ser Thr Ser
20 25 30
Ser Val Ile Arg Leu Asn Ser Pro Thr Thr Thr Ser Gln Ile Met Ala
35 40 45
Arg Lys Lys Arg Arg Gly Ile Ile Glu Lys Arg Arg Arg Asp Arg Ile
50 55 60
Asn Asn Ser Leu Ser Glu Leu Arg Arg Leu Val Pro Thr Ala Phe Glu
65 70 75 80
Lys Gln Gly Ser Ala Lys Leu Glu Lys Ala Glu Ile Leu Gln Met Thr
85 90 95
Val Asp His Leu Lys Met Leu Gln Ala Thr Gly Gly Lys Gly Tyr Phe
100 105 110
Asp Ala His Ala Leu Ala Met Asp Phe Met Ser Ile Gly Phe Arg Glu
115 120 125
Cys Leu Thr Glu Val Ala Arg Tyr Leu Ser Ser Val Glu Gly Leu Asp
130 135 140
Ser Ser Asp Pro Leu Arg Val Arg Leu Val Ser His Leu Ser Thr Cys
145 150 155 160
Ala Thr Gln Arg Glu Ala Ala Ala Met Thr Ser Ser Met Ala His His
165 170 175
His His Pro Leu His Pro His His Trp Ala Ala Ala Phe His His Leu
180 185 190
Pro Ala Ala Leu Leu Gln Pro Asn Gly Leu His Ala Ser Glu Ser Thr
195 200 205
Pro Cys Arg Leu Ser Thr Thr Ser Glu Val Pro Pro Ala His Gly Ser
210 215 220
Ala Leu Leu Thr Ala Thr Phe Ala His Ala Asp Ser Ala Leu Arg Met
225 230 235 240
Pro Ser Thr Gly Ser Val Ala Pro Cys Val Pro Pro Leu Ser Thr Ser
245 250 255
Leu Leu Ser Leu Ser Ala Thr Val His Ala Ala Ala Ala Ala Ala Thr
260 265 270
Ala Ala Ala His Ser Phe Pro Leu Ser Phe Ala Gly Ala Phe Pro Met
275 280 285
Leu Pro Pro Asn Ala Ala Ala Ala Val Ala Ala Ala Thr Ala Ile Ser
290 295 300
Pro Pro Leu Ser Val Ser Ala Thr Ser Ser Pro Gln Gln Thr Ser Ser
305 310 315 320
Gly Thr Asn Asn Lys Pro Tyr Arg Pro Trp Gly Thr Glu Val Gly Ala
325 330 335
Phe
<210> 60
<211> 553
<212> PRT
<213> 人类
<400> 60
Met Gln Ala Arg Tyr Ser Val Ser Ser Pro Asn Ser Leu Gly Val Val
1 5 10 15
Pro Tyr Leu Gly Gly Glu Gln Ser Tyr Tyr Arg Ala Ala Ala Ala Ala
20 25 30
Ala Gly Gly Gly Tyr Thr Ala Met Pro Ala Pro Met Ser Val Tyr Ser
35 40 45
His Pro Ala His Ala Glu Gln Tyr Pro Gly Gly Met Ala Arg Ala Tyr
50 55 60
Gly Pro Tyr Thr Pro Gln Pro Gln Pro Lys Asp Met Val Lys Pro Pro
65 70 75 80
Tyr Ser Tyr Ile Ala Leu Ile Thr Met Ala Ile Gln Asn Ala Pro Asp
85 90 95
Lys Lys Ile Thr Leu Asn Gly Ile Tyr Gln Phe Ile Met Asp Arg Phe
100 105 110
Pro Phe Tyr Arg Asp Asn Lys Gln Gly Trp Gln Asn Ser Ile Arg His
115 120 125
Asn Leu Ser Leu Asn Glu Cys Phe Val Lys Val Pro Arg Asp Asp Lys
130 135 140
Lys Pro Gly Lys Gly Ser Tyr Trp Thr Leu Asp Pro Asp Ser Tyr Asn
145 150 155 160
Met Phe Glu Asn Gly Ser Phe Leu Arg Arg Arg Arg Arg Phe Lys Lys
165 170 175
Lys Asp Ala Val Lys Asp Lys Glu Glu Lys Asp Arg Leu His Leu Lys
180 185 190
Glu Pro Pro Pro Pro Gly Arg Gln Pro Pro Pro Ala Pro Pro Glu Gln
195 200 205
Ala Asp Gly Asn Ala Pro Gly Pro Gln Pro Pro Pro Val Arg Ile Gln
210 215 220
Asp Ile Lys Thr Glu Asn Gly Thr Cys Pro Ser Pro Pro Gln Pro Leu
225 230 235 240
Ser Pro Ala Ala Ala Leu Gly Ser Gly Ser Ala Ala Ala Val Pro Lys
245 250 255
Ile Glu Ser Pro Asp Ser Ser Ser Ser Ser Leu Ser Ser Gly Ser Ser
260 265 270
Pro Pro Gly Ser Leu Pro Ser Ala Arg Pro Leu Ser Leu Asp Gly Ala
275 280 285
Asp Ser Ala Pro Pro Pro Pro Ala Pro Ser Ala Pro Pro Pro His His
290 295 300
Ser Gln Gly Phe Ser Val Asp Asn Ile Met Thr Ser Leu Arg Gly Ser
305 310 315 320
Pro Gln Ser Ala Ala Ala Glu Leu Ser Ser Gly Leu Leu Ala Ser Ala
325 330 335
Ala Ala Ser Ser Arg Ala Gly Ile Ala Pro Pro Leu Ala Leu Gly Ala
340 345 350
Tyr Ser Pro Gly Gln Ser Ser Leu Tyr Ser Ser Pro Cys Ser Gln Thr
355 360 365
Ser Ser Ala Gly Ser Ser Gly Gly Gly Gly Gly Gly Ala Gly Ala Ala
370 375 380
Gly Gly Ala Gly Gly Ala Gly Thr Tyr His Cys Asn Leu Gln Ala Met
385 390 395 400
Ser Leu Tyr Ala Ala Gly Glu Arg Gly Gly His Leu Gln Gly Ala Pro
405 410 415
Gly Gly Ala Gly Gly Ser Ala Val Asp Asp Pro Leu Pro Asp Tyr Ser
420 425 430
Leu Pro Pro Val Thr Ser Ser Ser Ser Ser Ser Leu Ser His Gly Gly
435 440 445
Gly Gly Gly Gly Gly Gly Gly Gly Gln Glu Ala Gly His His Pro Ala
450 455 460
Ala His Gln Gly Arg Leu Thr Ser Trp Tyr Leu Asn Gln Ala Gly Gly
465 470 475 480
Asp Leu Gly His Leu Ala Ser Ala Ala Ala Ala Ala Ala Ala Ala Gly
485 490 495
Tyr Pro Gly Gln Gln Gln Asn Phe His Ser Val Arg Glu Met Phe Glu
500 505 510
Ser Gln Arg Ile Gly Leu Asn Asn Ser Pro Val Asn Gly Asn Ser Ser
515 520 525
Cys Gln Met Ala Phe Pro Ser Ser Gln Ser Leu Tyr Arg Thr Ser Gly
530 535 540
Ala Phe Val Tyr Asp Cys Ser Lys Phe
545 550
<210> 61
<211> 501
<212> PRT
<213> 人类
<400> 61
Met Gln Ala Arg Tyr Ser Val Ser Asp Pro Asn Ala Leu Gly Val Val
1 5 10 15
Pro Tyr Leu Ser Glu Gln Asn Tyr Tyr Arg Ala Ala Gly Ser Tyr Gly
20 25 30
Gly Met Ala Ser Pro Met Gly Val Tyr Ser Gly His Pro Glu Gln Tyr
35 40 45
Ser Ala Gly Met Gly Arg Ser Tyr Ala Pro Tyr His His His Gln Pro
50 55 60
Ala Ala Pro Lys Asp Leu Val Lys Pro Pro Tyr Ser Tyr Ile Ala Leu
65 70 75 80
Ile Thr Met Ala Ile Gln Asn Ala Pro Glu Lys Lys Ile Thr Leu Asn
85 90 95
Gly Ile Tyr Gln Phe Ile Met Asp Arg Phe Pro Phe Tyr Arg Glu Asn
100 105 110
Lys Gln Gly Trp Gln Asn Ser Ile Arg His Asn Leu Ser Leu Asn Glu
115 120 125
Cys Phe Val Lys Val Pro Arg Asp Asp Lys Lys Pro Gly Lys Gly Ser
130 135 140
Tyr Trp Thr Leu Asp Pro Asp Ser Tyr Asn Met Phe Glu Asn Gly Ser
145 150 155 160
Phe Leu Arg Arg Arg Arg Arg Phe Lys Lys Lys Asp Val Ser Lys Glu
165 170 175
Lys Glu Glu Arg Ala His Leu Lys Glu Pro Pro Pro Ala Ala Ser Lys
180 185 190
Gly Ala Pro Ala Thr Pro His Leu Ala Asp Ala Pro Lys Glu Ala Glu
195 200 205
Lys Lys Val Val Ile Lys Ser Glu Ala Ala Ser Pro Ala Leu Pro Val
210 215 220
Ile Thr Lys Val Glu Thr Leu Ser Pro Glu Ser Ala Leu Gln Gly Ser
225 230 235 240
Pro Arg Ser Ala Ala Ser Thr Pro Ala Gly Ser Pro Asp Gly Ser Leu
245 250 255
Pro Glu His His Ala Ala Ala Pro Asn Gly Leu Pro Gly Phe Ser Val
260 265 270
Glu Asn Ile Met Thr Leu Arg Thr Ser Pro Pro Gly Gly Glu Leu Ser
275 280 285
Pro Gly Ala Gly Arg Ala Gly Leu Val Val Pro Pro Leu Ala Leu Pro
290 295 300
Tyr Ala Ala Ala Pro Pro Ala Ala Tyr Gly Gln Pro Cys Ala Gln Gly
305 310 315 320
Leu Glu Ala Gly Ala Ala Gly Gly Tyr Gln Cys Ser Met Arg Ala Met
325 330 335
Ser Leu Tyr Thr Gly Ala Glu Arg Pro Ala His Met Cys Val Pro Pro
340 345 350
Ala Leu Asp Glu Ala Leu Ser Asp His Pro Ser Gly Pro Thr Ser Pro
355 360 365
Leu Ser Ala Leu Asn Leu Ala Ala Gly Gln Glu Gly Ala Leu Ala Ala
370 375 380
Thr Gly His His His Gln His His Gly His His His Pro Gln Ala Pro
385 390 395 400
Pro Pro Pro Pro Ala Pro Gln Pro Gln Pro Thr Pro Gln Pro Gly Ala
405 410 415
Ala Ala Ala Gln Ala Ala Ser Trp Tyr Leu Asn His Ser Gly Asp Leu
420 425 430
Asn His Leu Pro Gly His Thr Phe Ala Ala Gln Gln Gln Thr Phe Pro
435 440 445
Asn Val Arg Glu Met Phe Asn Ser His Arg Leu Gly Ile Glu Asn Ser
450 455 460
Thr Leu Gly Glu Ser Gln Val Ser Gly Asn Ala Ser Cys Gln Leu Pro
465 470 475 480
Tyr Arg Ser Thr Pro Pro Leu Tyr Arg His Ala Ala Pro Tyr Ser Tyr
485 490 495
Asp Cys Thr Lys Tyr
500
<210> 62
<211> 388
<212> PRT
<213> 人类
<400> 62
Met Ala Ser Leu Leu Gly Ala Tyr Pro Trp Pro Glu Gly Leu Glu Cys
1 5 10 15
Pro Ala Leu Asp Ala Glu Leu Ser Asp Gly Gln Ser Pro Pro Ala Val
20 25 30
Pro Arg Pro Pro Gly Asp Lys Gly Ser Glu Ser Arg Ile Arg Arg Pro
35 40 45
Met Asn Ala Phe Met Val Trp Ala Lys Asp Glu Arg Lys Arg Leu Ala
50 55 60
Val Gln Asn Pro Asp Leu His Asn Ala Glu Leu Ser Lys Met Leu Gly
65 70 75 80
Lys Ser Trp Lys Ala Leu Thr Leu Ser Gln Lys Arg Pro Tyr Val Asp
85 90 95
Glu Ala Glu Arg Leu Arg Leu Gln His Met Gln Asp Tyr Pro Asn Tyr
100 105 110
Lys Tyr Arg Pro Arg Arg Lys Lys Gln Ala Lys Arg Leu Cys Lys Arg
115 120 125
Val Asp Pro Gly Phe Leu Leu Ser Ser Leu Ser Arg Asp Gln Asn Ala
130 135 140
Leu Pro Glu Lys Arg Ser Gly Ser Arg Gly Ala Leu Gly Glu Lys Glu
145 150 155 160
Asp Arg Gly Glu Tyr Ser Pro Gly Thr Ala Leu Pro Ser Leu Arg Gly
165 170 175
Cys Tyr His Glu Gly Pro Ala Gly Gly Gly Gly Gly Gly Thr Pro Ser
180 185 190
Ser Val Asp Thr Tyr Pro Tyr Gly Leu Pro Thr Pro Pro Glu Met Ser
195 200 205
Pro Leu Asp Val Leu Glu Pro Glu Gln Thr Phe Phe Ser Ser Pro Cys
210 215 220
Gln Glu Glu His Gly His Pro Arg Arg Ile Pro His Leu Pro Gly His
225 230 235 240
Pro Tyr Ser Pro Glu Tyr Ala Pro Ser Pro Leu His Cys Ser His Pro
245 250 255
Leu Gly Ser Leu Ala Leu Gly Gln Ser Pro Gly Val Ser Met Met Ser
260 265 270
Pro Val Pro Gly Cys Pro Pro Ser Pro Ala Tyr Tyr Ser Pro Ala Thr
275 280 285
Tyr His Pro Leu His Ser Asn Leu Gln Ala His Leu Gly Gln Leu Ser
290 295 300
Pro Pro Pro Glu His Pro Gly Phe Asp Ala Leu Asp Gln Leu Ser Gln
305 310 315 320
Val Glu Leu Leu Gly Asp Met Asp Arg Asn Glu Phe Asp Gln Tyr Leu
325 330 335
Asn Thr Pro Gly His Pro Asp Ser Ala Thr Gly Ala Met Ala Leu Ser
340 345 350
Gly His Val Pro Val Ser Gln Val Thr Pro Thr Gly Pro Thr Glu Thr
355 360 365
Ser Leu Ile Ser Val Leu Ala Asp Ala Thr Ala Thr Tyr Tyr Asn Ser
370 375 380
Tyr Ser Val Ser
385
<210> 63
<211> 384
<212> PRT
<213> 人类
<400> 63
Met Gln Arg Ser Pro Pro Gly Tyr Gly Ala Gln Asp Asp Pro Pro Ala
1 5 10 15
Arg Arg Asp Cys Ala Trp Ala Pro Gly His Gly Ala Ala Ala Asp Thr
20 25 30
Arg Gly Leu Ala Ala Gly Pro Ala Ala Leu Ala Ala Pro Ala Ala Pro
35 40 45
Ala Ser Pro Pro Ser Pro Gln Arg Ser Pro Pro Arg Ser Pro Glu Pro
50 55 60
Gly Arg Tyr Gly Leu Ser Pro Ala Gly Arg Gly Glu Arg Gln Ala Ala
65 70 75 80
Asp Glu Ser Arg Ile Arg Arg Pro Met Asn Ala Phe Met Val Trp Ala
85 90 95
Lys Asp Glu Arg Lys Arg Leu Ala Gln Gln Asn Pro Asp Leu His Asn
100 105 110
Ala Val Leu Ser Lys Met Leu Gly Lys Ala Trp Lys Glu Leu Asn Ala
115 120 125
Ala Glu Lys Arg Pro Phe Val Glu Glu Ala Glu Arg Leu Arg Val Gln
130 135 140
His Leu Arg Asp His Pro Asn Tyr Lys Tyr Arg Pro Arg Arg Lys Lys
145 150 155 160
Gln Ala Arg Lys Ala Arg Arg Leu Glu Pro Gly Leu Leu Leu Pro Gly
165 170 175
Leu Ala Pro Pro Gln Pro Pro Pro Glu Pro Phe Pro Ala Ala Ser Gly
180 185 190
Ser Ala Arg Ala Phe Arg Glu Leu Pro Pro Leu Gly Ala Glu Phe Asp
195 200 205
Gly Leu Gly Leu Pro Thr Pro Glu Arg Ser Pro Leu Asp Gly Leu Glu
210 215 220
Pro Gly Glu Ala Ala Phe Phe Pro Pro Pro Ala Ala Pro Glu Asp Cys
225 230 235 240
Ala Leu Arg Pro Phe Arg Ala Pro Tyr Ala Pro Thr Glu Leu Ser Arg
245 250 255
Asp Pro Gly Gly Cys Tyr Gly Ala Pro Leu Ala Glu Ala Leu Arg Thr
260 265 270
Ala Pro Pro Ala Ala Pro Leu Ala Gly Leu Tyr Tyr Gly Thr Leu Gly
275 280 285
Thr Pro Gly Pro Tyr Pro Gly Pro Leu Ser Pro Pro Pro Glu Ala Pro
290 295 300
Pro Leu Glu Ser Ala Glu Pro Leu Gly Pro Ala Ala Asp Leu Trp Ala
305 310 315 320
Asp Val Asp Leu Thr Glu Phe Asp Gln Tyr Leu Asn Cys Ser Arg Thr
325 330 335
Arg Pro Asp Ala Pro Gly Leu Pro Tyr His Val Ala Leu Ala Lys Leu
340 345 350
Gly Pro Arg Ala Met Ser Cys Pro Glu Glu Ser Ser Leu Ile Ser Ala
355 360 365
Leu Ser Asp Ala Ser Ser Ala Val Tyr Tyr Ser Ala Cys Ile Ser Gly
370 375 380
<210> 64
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> his tag
<400> 64
His His His His His His Ser Ser
1 5
<210> 65
<211> 954
<212> DNA
<213> 人类
<400> 65
atgtacaaca tgatggagac ggagctgaag ccgccgggcc cgcagcaaac ttcggggggc 60
ggcggcggca actccaccgc ggcggcggcc ggcggcaacc agaaaaacag cccggaccgc 120
gtcaagcggc ccatgaatgc cttcatggtg tggtcccgcg ggcagcggcg caagatggcc 180
caggagaacc ccaagatgca caactcggag atcagcaagc gcctgggcgc cgagtggaaa 240
cttttgtcgg agacggagaa gcggccgttc atcgacgagg ctaagcggct gcgagcgctg 300
cacatgaagg agcacccgga ttataaatac cggccccggc ggaaaaccaa gacgctcatg 360
aagaaggata agtacacgct gcccggcggg ctgctggccc ccggcggcaa tagcatggcg 420
agcggggtcg gggtgggcgc cggcctgggc gcgggcgtga accagcgcat ggacagttac 480
gcgcacatga acggctggag caacggcagc tacagcatga tgcaggacca gctgggctac 540
ccgcagcacc cgggcctcaa tgcgcacggc gcagcgcaga tgcagcccat gcaccgctac 600
gacgtgagcg ccctgcagta caactccatg accagctcgc agacctacat gaacggctcg 660
cccacctaca gcatgtccta ctcgcagcag ggcacccctg gcatggctct tggctccatg 720
ggttcggtgg tcaagtccga ggccagctcc agcccccctg tggttacctc ttcctcccac 780
tccagggcgc cctgccaggc cggggacctc cgggacatga tcagcatgta tctccccggc 840
gccgaggtgc cggaacccgc cgcccccagc agacttcaca tgtcccagca ctaccagagc 900
ggcccggtgc ccggcacggc cattaacggc acactgcccc tctcacacat gtga 954
<210> 66
<211> 1083
<212> DNA
<213> 人类
<400> 66
atggcgggac acctggcttc ggatttcgcc ttctcgcccc ctccaggtgg tggaggtgat 60
gggccagggg ggccggagcc gggctgggtt gatcctcgga cctggctaag cttccaaggc 120
cctcctggag ggccaggaat cgggccgggg gttgggccag gctctgaggt gtgggggatt 180
cccccatgcc ccccgccgta tgagttctgt ggggggatgg cgtactgtgg gccccaggtt 240
ggagtggggc tagtgcccca aggcggcttg gagacctctc agcctgaggg cgaagcagga 300
gtcggggtgg agagcaactc cgatggggcc tccccggagc cctgcaccgt cacccctggt 360
gccgtgaagc tggagaagga gaagctggag caaaacccgg aggagtccca ggacatcaaa 420
gctctgcaga aagaactcga gcaatttgcc aagctcctga agcagaagag gatcaccctg 480
ggatatacac aggccgatgt ggggctcacc ctgggggttc tatttgggaa ggtattcagc 540
caaacgacca tctgccgctt tgaggctctg cagcttagct tcaagaacat gtgtaagctg 600
cggcccttgc tgcagaagtg ggtggaggaa gctgacaaca atgaaaatct tcaggagata 660
tgcaaagcag aaaccctcgt gcaggcccga aagagaaagc gaaccagtat cgagaaccga 720
gtgagaggca acctggagaa tttgttcctg cagtgcccga aacccacact gcagcagatc 780
agccacatcg cccagcagct tgggctcgag aaggatgtgg tccgagtgtg gttctgtaac 840
cggcgccaga agggcaagcg atcaagcagc gactatgcac aacgagagga ttttgaggct 900
gctgggtctc ctttctcagg gggaccagtg tcctttcctc tggccccagg gccccatttt 960
ggtaccccag gctatgggag ccctcacttc actgcactgt actcctcggt ccctttccct 1020
gagggggaag cctttccccc tgtctccgtc accactctgg gctctcccat gcattcaaac 1080
tga 1083
<210> 67
<211> 918
<212> DNA
<213> 人类
<400> 67
atgagtgtgg atccagcttg tccccaaagc ttgccttgct ttgaagcatc cgactgtaaa 60
gaatcttcac ctatgcctgt gatttgtggg cctgaagaaa actatccatc cttgcaaatg 120
tcttctgctg agatgcctca cacggagact gtctctcctc ttccttcctc catggatctg 180
cttattcagg acagccctga ttcttccacc agtcccaaag gcaaacaacc cacttctgca 240
gagaagagtg tcgcaaaaaa ggaagacaag gtcccggtca agaaacagaa gaccagaact 300
gtgttctctt ccacccagct gtgtgtactc aatgatagat ttcagagaca gaaatacctc 360
agcctccagc agatgcaaga actctccaac atcctgaacc tcagctacaa acaggtgaag 420
acctggttcc agaaccagag aatgaaatct aagaggtggc agaaaaacaa ctggccgaag 480
aatagcaatg gtgtgacgca gaaggcctca gcacctacct accccagcct ttactcttcc 540
taccaccagg gatgcctggt gaacccgact gggaaccttc caatgtggag caaccagacc 600
tggaacaatt caacctggag caaccagacc cagaacatcc agtcctggag caaccactcc 660
tggaacactc agacctggtg cacccaatcc tggaacaatc aggcctggaa cagtcccttc 720
tataactgtg gagaggaatc tctgcagtcc tgcatgcagt tccagccaaa ttctcctgcc 780
agtgacttgg aggctgcctt ggaagctgct ggggaaggcc ttaatgtaat acagcagacc 840
actaggtatt ttagtactcc acaaaccatg gatttattcc taaactactc catgaacatg 900
caacctgaag acgtgtga 918
<210> 68
<211> 630
<212> DNA
<213> 人类
<400> 68
atgggctccg tgtccaacca gcagtttgca ggtggctgcg ccaaggcggc agaagaggcg 60
cccgaggagg cgccggagga cgcggcccgg gcggcggacg agcctcagct gctgcacggt 120
gcgggcatct gtaagtggtt caacgtgcgc atggggttcg gcttcctgtc catgaccgcc 180
cgcgccgggg tcgcgctcga ccccccagtg gatgtctttg tgcaccagag taagctgcac 240
atggaagggt tccggagctt gaaggagggt gaggcagtgg agttcacctt taagaagtca 300
gccaagggtc tggaatccat ccgtgtcacc ggacctggtg gagtattctg tattgggagt 360
gagaggcggc caaaaggaaa gagcatgcag aagcgcagat caaaaggaga caggtgctac 420
aactgtggag gtctagatca tcatgccaag gaatgcaagc tgccacccca gcccaagaag 480
tgccacttct gccagagcat cagccatatg gtagcctcat gtccgctgaa ggcccagcag 540
ggccctagtg cacagggaaa gccaacctac tttcgagagg aagaagaaga aatccacagc 600
cctaccctgc tcccggaggc acagaattga 630
<210> 69
<211> 1440
<212> DNA
<213> 人类
<400> 69
atgaggcagc cacctggcga gtctgacatg gctgtcagcg acgcgctgct cccatctttc 60
tccacgttcg cgtctggccc ggcgggaagg gagaagacac tgcgtcaagc aggtgccccg 120
aataaccgct ggcgggagga gctctcccac atgaagcgac ttcccccagt gcttcccggc 180
cgcccctatg acctggcggc ggcgaccgtg gccacagacc tggagagcgg cggagccggt 240
gcggcttgcg gcggtagcaa cctggcgccc ctacctcgga gagagaccga ggagttcaac 300
gatctcctgg acctggactt tattctctcc aattcgctga cccatcctcc ggagtcagtg 360
gccgccaccg tgtcctcgtc agcgtcagcc tcctcttcgt cgtcgccgtc gagcagcggc 420
cctgccagcg cgccctccac ctgcagcttc acctatccga tccgggccgg gaacgacccg 480
ggcgtggcgc cgggcggcac gggcggaggc ctcctctatg gcagggagtc cgctccccct 540
ccgacggctc ccttcaacct ggcggacatc aacgacgtga gcccctcggg cggcttcgtg 600
gccgagctcc tgcggccaga attggacccg gtgtacattc cgccgcagca gccgcagccg 660
ccaggtggcg ggctgatggg caagttcgtg ctgaaggcgt cgctgagcgc ccctggcagc 720
gagtacggca gcccgtcggt catcagcgtc agcaaaggca gccctgacgg cagccacccg 780
gtggtggtgg cgccctacaa cggcgggccg ccgcgcacgt gccccaagat caagcaggag 840
gcggtctctt cgtgcaccca cttgggcgct ggaccccctc tcagcaatgg ccaccggccg 900
gctgcacacg acttccccct ggggcggcag ctccccagca ggactacccc gaccctgggt 960
cttgaggaag tgctgagcag cagggactgt caccctgccc tgccgcttcc tcccggcttc 1020
catccccacc cggggcccaa ttacccatcc ttcctgcccg atcagatgca gccgcaagtc 1080
ccgccgctcc attaccaaga gctcatgcca cccggttcct gcatgccaga ggagcccaag 1140
ccaaagaggg gaagacgatc gtggccccgg aaaaggaccg ccacccacac ttgtgattac 1200
gcgggctgcg gcaaaaccta cacaaagagt tcccatctca aggcacacct gcgaacccac 1260
acaggtgaga aaccttacca ctgtgactgg gacggctgtg gatggaaatt cgcccgctca 1320
gatgaactga ccaggcacta ccgtaaacac acggggcacc gcccgttcca gtgccaaaaa 1380
tgcgaccgag cattttccag gtcggaccac ctcgccttac acatgaagag gcatttttaa 1440
<210> 70
<211> 1365
<212> DNA
<213> 人类
<400> 70
ctggattttt ttcgggtagt ggaaaaccag cagcctcccg cgacgatgcc cctcaacgtt 60
agcttcacca acaggaacta tgacctcgac tacgactcgg tgcagccgta tttctactgc 120
gacgaggagg agaacttcta ccagcagcag cagcagagcg agctgcagcc cccggcgccc 180
agcgaggata tctggaagaa attcgagctg ctgcccaccc cgcccctgtc ccctagccgc 240
cgctccgggc tctgctcgcc ctcctacgtt gcggtcacac ccttctccct tcggggagac 300
aacgacggcg gtggcgggag cttctccacg gccgaccagc tggagatggt gaccgagctg 360
ctgggaggag acatggtgaa ccagagtttc atctgcgacc cggacgacga gaccttcatc 420
aaaaacatca tcatccagga ctgtatgtgg agcggcttct cggccgccgc caagctcgtc 480
tcagagaagc tggcctccta ccaggctgcg cgcaaagaca gcggcagccc gaaccccgcc 540
cgcggccaca gcgtctgctc cacctccagc ttgtacctgc aggatctgag cgccgccgcc 600
tcagagtgca tcgacccctc ggtggtcttc ccctaccctc tcaacgacag cagctcgccc 660
aagtcctgcg cctcgcaaga ctccagcgcc ttctctccgt cctcggattc tctgctctcc 720
tcgacggagt cctccccgca gggcagcccc gagcccctgg tgctccatga ggagacaccg 780
cccaccacca gcagcgactc tgaggaggaa caagaagatg aggaagaaat cgatgttgtt 840
tctgtggaaa agaggcaggc tcctggcaaa aggtcagagt ctggatcacc ttctgctgga 900
ggccacagca aacctcctca cagcccactg gtcctcaaga ggtgccacgt ctccacacat 960
cagcacaact acgcagcgcc tccctccact cggaaggact atcctgctgc caagagggtc 1020
aagttggaca gtgtcagagt cctgagacag atcagcaaca accgaaaatg caccagcccc 1080
aggtcctcgg acaccgagga gaatgtcaag aggcgaacac acaacgtctt ggagcgccag 1140
aggaggaacg agctaaaacg gagctttttt gccctgcgtg accagatccc ggagttggaa 1200
aacaatgaaa aggcccccaa ggtagttatc cttaaaaaag ccacagcata catcctgtcc 1260
gtccaagcag aggagcaaaa gctcatttct gaagaggact tgttgcggaa acgacgagaa 1320
cagttgaaac acaaacttga acagctacgg aactcttgtg cgtaa 1365
<210> 71
<211> 1329
<212> DNA
<213> 人类
<400> 71
atgtatcaga gcttggccat ggccgccaac cacgggccgc cccccggtgc ctacgaggcg 60
ggcggccccg gcgccttcat gcacggcgcg ggcgccgcgt cctcgccagt ctacgtgccc 120
acaccgcggg tgccctcctc cgtgctgggc ctgtcctacc tccagggcgg aggcgcgggc 180
tctgcgtccg gaggcgcctc gggcggcagc tccggtgggg ccgcgtctgg tgcggggccc 240
gggacccagc agggcagccc gggatggagc caggcgggag ccgacggagc cgcttacacc 300
ccgccgccgg tgtcgccgcg cttctccttc ccggggacca ccgggtccct ggcggccgcc 360
gccgccgctg ccgcggcccg ggaagctgcg gcctacagca gtggcggcgg agcggcgggt 420
gcgggcctgg cgggccgcga gcagtacggg cgcgccggct tcgcgggctc ctactccagc 480
ccctacccgg cttacatggc cgacgtgggc gcgtcctggg ccgcagccgc cgccgcctcc 540
gccggcccct tcgacagccc ggtcctgcac agcctgcccg gccgggccaa cccggccgcc 600
cgacacccca atctcgatat gtttgacgac ttctcagaag gcagagagtg tgtcaactgt 660
ggggctatgt ccaccccgct ctggaggcga gatgggacgg gtcactatct gtgcaacgcc 720
tgcggcctct accacaagat gaacggcatc aaccggccgc tcatcaagcc tcagcgccgg 780
ctgtccgcct cccgccgagt gggcctctcc tgtgccaact gccagaccac caccaccacg 840
ctgtggcgcc gcaatgcgga gggcgagcct gtgtgcaatg cctgcggcct ctacatgaag 900
ctccacgggg tccccaggcc tcttgcaatg cggaaagagg ggatccaaac cagaaaacgg 960
aagcccaaga acctgaataa atctaagaca ccagcagctc cttcaggcag tgagagcctt 1020
cctcccgcca gcggtgcttc cagcaactcc agcaacgcca ccaccagcag cagcgaggag 1080
atgcgtccca tcaagacgga gcctggcctg tcatctcact acgggcacag cagctccgtg 1140
tcccagacgt tctcagtcag tgcgatgtct ggccatgggc cctccatcca ccctgtcctc 1200
tcggccctga agctctcccc acaaggctat gcgtctcccg tcagccagtc tccacagacc 1260
agctccaagc aggactcttg gaacagcctg gtcttggccg acagtcacgg ggacataatc 1320
actgcgtaa 1329
<210> 72
<211> 654
<212> DNA
<213> 人类
<400> 72
atgagtctgg taggtggttt tccccaccac ccggtggtgc accacgaggg ctacccgttt 60
gccgccgccg ccgccgcagc tgccgccgcc gccgccagcc gctgcagcca tgaggagaac 120
ccctacttcc atggctggct catcggccac cccgagatgt cgccccccga ctacagcatg 180
gccctgtcct acagccccga gtatgccagc ggcgccgccg gcctggacca ctcccattac 240
gggggggtgc cgccgggcgc cgggcccccg ggcctggggg ggccgcgccc ggtgaagcgc 300
cgaggcaccg ccaaccgcaa ggagcggcgc aggactcaga gcatcaacag cgccttcgcc 360
gaactgcgcg agtgcatccc caacgtaccc gccgacacca aactctccaa aatcaagacc 420
ctgcgcctgg ccaccagcta catcgcctac ctcatggacc tgctggccaa ggacgaccag 480
aatggcgagg cggaggcctt caaggcagag atcaagaaga ccgacgtgaa agaggagaag 540
aggaagaagg agctgaacga aatcttgaaa agcacagtga gcagcaacga caagaaaacc 600
aaaggccgga cgggctggcc gcagcacgtc tgggccctgg agctcaagca gtga 654
<210> 73
<211> 1422
<212> DNA
<213> 人类
<400> 73
atggggagaa aaaagattca gattacgagg attatggatg aacgtaacag acaggtgaca 60
tttacaaaga ggaaatttgg gttgatgaag aaggcttatg agctgagcgt gctgtgtgac 120
tgtgagattg cgctgatcat cttcaacagc accaacaagc tgttccagta tgccagcacc 180
gacatggaca aagtgcttct caagtacacg gagtacaacg agccgcatga gagccggaca 240
aactcagaca tcgtggagac gttgagaaag aagggcctta atggctgtga cagcccagac 300
cccgatgcgg acgattccgt aggtcacagc cctgagtctg aggacaagta caggaaaatt 360
aacgaagata ttgatctaat gatcagcagg caaagattgt gtgctgttcc acctcccaac 420
ttcgagatgc cagtctccat cccagtgtcc agccacaaca gtttggtgta cagcaaccct 480
gtcagctcac tgggaaaccc caacctattg ccactggctc acccttctct gcagaggaat 540
agtatgtctc ctggtgtaac acatcgacct ccaagtgcag gtaacacagg tggtctgatg 600
ggtggagacc tcacgtctgg tgcaggcacc agtgcaggga acgggtatgg caatccccga 660
aactcaccag gtctgctggt ctcacctggt aacttgaaca agaatatgca agcaaaatct 720
cctcccccaa tgaatttagg aatgaataac cgtaaaccag atctccgagt tcttattcca 780
ccaggcagca agaatacgat gccatcagtg tctgaggatg tcgacctgct tttgaatcaa 840
aggataaata actcccagtc ggctcagtca ttggctaccc cagtggtttc cgtagcaact 900
cctactttac caggacaagg aatgggagga tatccatcag ccatttcaac aacatatggt 960
accgagtact ctctgagtag tgcagacctg tcatctctgt ctgggtttaa caccgccagc 1020
gctcttcacc ttggttcagt aactggctgg caacagcaac acctacataa catgccacca 1080
tctgccctca gtcagttggg agcttgcact agcactcatt tatctcagag ttcaaatctc 1140
tccctgcctt ctactcaaag cctcaacatc aagtcagaac ctgtttctcc tcctagagac 1200
cgtaccacca ccccttcgag atacccacaa cacacgcgcc acgaggcggg gagatctcct 1260
gttgacagct tgagcagctg tagcagttcg tacgacggga gcgaccgaga ggatcaccgg 1320
aacgaattcc actcccccat tggactcacc agaccttcgc cggacgaaag ggaaagtccc 1380
tcagtcaagc gcatgcgact ttctgaagga tgggcaacat ga 1422
<210> 74
<211> 1050
<212> DNA
<213> 人类
<400> 74
atggccgacg cagacgaggg ctttggcctg gcgcacacgc ctctggagcc tgacgcaaaa 60
gacctgccct gcgattcgaa acccgagagc gcgctcgggg cccccagcaa gtccccgtcg 120
tccccgcagg ccgccttcac ccagcagggc atggagggaa tcaaagtgtt tctccatgaa 180
agagaactgt ggctaaaatt ccacgaagtg ggcacggaaa tgatcataac caaggctgga 240
aggcggatgt ttcccagtta caaagtgaag gtgacgggcc ttaatcccaa aacgaagtac 300
attcttctca tggacattgt acctgccgac gatcacagat acaaattcgc agataataaa 360
tggtctgtga cgggcaaagc tgagcccgcc atgcctggcc gcctgtacgt gcacccagac 420
tcccccgcca ccggggcgca ttggatgagg cagctcgtct ccttccagaa actcaagctc 480
accaacaacc acctggaccc atttgggcat attattctaa attccatgca caaataccag 540
cctagattac acatcgtgaa agcggatgaa aataatggat ttggctcaaa aaatacagcg 600
ttctgcactc acgtctttcc tgagactgcg tttatagcag tgacttccta ccagaaccac 660
aagatcacgc aattaaagat tgagaataat ccctttgcca aaggatttcg gggcagtgat 720
gacatggagc tgcacagaat gtcaagaatg caaagtaaag aatatcccgt ggtccccagg 780
agcaccgtga ggcaaaaagt ggcctccaac cacagtcctt tcagcagcga gtctcgagct 840
ctctccacct catccaattt ggggtcccaa taccagtgtg agaatggtgt ttccggcccc 900
tcccaggacc tcctgcctcc acccaaccca tacccactgc cccaggagca tagccaaatt 960
taccattgta ccaagaggaa aggtgagtgt gatcacccct ggtcaatttg ctttctttct 1020
taccttttcc tttccttggg ttgggggtga 1050
<210> 75
<211> 645
<212> DNA
<213> 人类
<400> 75
atgacgcctc aaccctcggg tgcgcccact gtccaagtga cccgtgagac ggagcggtcc 60
ttccccagag cctcggaaga cgaagtgacc tgccccacgt ccgccccgcc cagccccact 120
cgcacacggg ggaactgcgc agaggcggaa gagggaggct gccgaggggc cccgaggaag 180
ctccgggcac ggcgcggggg acgcagccgg cctaagagcg agttggcact gagcaagcag 240
cgacggagtc ggcgaaagaa ggccaacgac cgcgagcgca atcgaatgca caacctcaac 300
tcggcactgg acgccctgcg cggtgtcctg cccaccttcc cagacgacgc gaagctcacc 360
aagatcgaga cgctgcgctt cgcccacaac tacatctggg cgctgactca aacgctgcgc 420
atagcggacc acagcttgta cgcgctggag ccgccggcgc cgcactgcgg ggagctgggc 480
agcccaggcg gttcccccgg ggactggggg tccctctact ccccagtctc ccaggctggc 540
agcctgagtc ccgccgcgtc gctggaggag cgacccgggc tgctgggggc caccttttcc 600
gcctgcttga gcccaggcag tctggctttc tcagattttc tgtga 645
<210> 76
<211> 1032
<212> DNA
<213> 人类
<400> 76
atgaaccagc ttggggggct ctttgtgaat ggccggcccc tgcctctgga tacccggcag 60
cagattgtgc ggctagcagt cagtggaatg cggccctgtg acatctcacg gatccttaag 120
gtatctaatg gctgtgtgag caagatccta gggcgttact accgcacagg tgtcttggag 180
ccaaagggca ttgggggaag caagccacgg ctggctacac cccctgtggt ggctcgaatt 240
gcccagctga agggtgagtg tccagccctc tttgcctggg aaatccaacg ccagctttgt 300
gctgaagggc tttgcaccca ggacaagact cccagtgtct cctccatcaa ccgagtcctg 360
cgggcattac aggaggacca gggactaccg tgcacacggc tcaggtcacc agctgttttg 420
gctccagctg tcctcactcc ccatagtggc tctgagactc cccggggtac ccacccaggg 480
accggccacc ggaatcggac tatcttctcc ccaagccaag cagaggcact ggagaaagag 540
ttccagcgtg ggcagtatcc tgattcagtg gcccgtggaa agctggctac tgccacctct 600
ctgcctgagg acacggtgag ggtctggttt tccaacagaa gagccaaatg gcgtcggcaa 660
gagaagctca agtgggaaat gcagctgcca ggtgcttccc aggggctgac tgtaccaagg 720
gttgccccag gaatcatctc tgcacagcag tcccctggca gtgtgcccac agcagccctg 780
cctgccctgg aaccactggg tccctcctgc tatcagctgt gctgggcaac agcaccagaa 840
aggtgtctga gtgacacccc acctaaagcc tgtctcaagc cctgctgggg ccacttgccc 900
ccacagccga attccctgga ctcaggactg ctttgccttc cttgcccttc ctcccactgt 960
cacctggcca gtcttagtgg ctctcaggcc ctgctctggc ctggctgccc actactgtat 1020
ggcttggaat ga 1032
<210> 77
<211> 852
<212> DNA
<213> 人类
<400> 77
atgaacggcg aggagcagta ctacgcggcc acgcagcttt acaaggaccc atgcgcgttc 60
cagcgaggcc cggcgccgga gttcagcgcc agcccccctg cgtgcctgta catgggccgc 120
cagcccccgc cgccgccgcc gcacccgttc cctggcgccc tgggcgcgct ggagcagggc 180
agccccccgg acatctcccc gtacgaggtg ccccccctcg ccgacgaccc cgcggtggcg 240
caccttcacc accacctccc ggctcagctc gcgctccccc acccgcccgc cgggcccttc 300
ccggagggag ccgagccggg cgtcctggag gagcccaacc gcgtccagct gcctttccca 360
tggatgaagt ctaccaaagc tcacgcgtgg aaaggccagt gggcaggcgg cgcctacgct 420
gcggagccgg aggagaacaa gcggacgcgc acggcctaca cgcgcgcaca gctgctagag 480
ctggagaagg agttcctatt caacaagtac atctcacggc cgcgccgggt ggagctggct 540
gtcatgttga acttgaccga gagacacatc aagatctggt tccaaaaccg ccgcatgaag 600
tggaaaaagg aggaggacaa gaagcgcggc ggcgggacag ctgtcggggg tggcggggtc 660
gcggagcctg agcaggactg cgccgtgacc tccggcgagg agcttctggc gctgccgccg 720
ccgccgcccc ccggaggtgc tgtgccgccc gctgcccccg ttgccgcccg agagggccgc 780
ctgccgcctg gccttagcgc gtcgccacag ccctccagcg tcgcgcctcg gcggccgcag 840
gaaccacgat ga 852
<210> 78
<211> 1530
<212> DNA
<213> 人类
<400> 78
atgaatctcc tggacccctt catgaagatg accgacgagc aggagaaggg cctgtccggc 60
gcccccagcc ccaccatgtc cgaggactcc gcgggctcgc cctgcccgtc gggctccggc 120
tcggacaccg agaacacgcg gccccaggag aacacgttcc ccaagggcga gcccgatctg 180
aagaaggaga gcgaggagga caagttcccc gtgtgcatcc gcgaggcggt cagccaggtg 240
ctcaaaggct acgactggac gctggtgccc atgccggtgc gcgtcaacgg ctccagcaag 300
aacaagccgc acgtcaagcg gcccatgaac gccttcatgg tgtgggcgca ggcggcgcgc 360
aggaagctcg cggaccagta cccgcacttg cacaacgccg agctcagcaa gacgctgggc 420
aagctctgga gacttctgaa cgagagcgag aagcggccct tcgtggagga ggcggagcgg 480
ctgcgcgtgc agcacaagaa ggaccacccg gattacaagt accagccgcg gcggaggaag 540
tcggtgaaga acgggcaggc ggaggcagag gaggccacgg agcagacgca catctccccc 600
aacgccatct tcaaggcgct gcaggccgac tcgccacact cctcctccgg catgagcgag 660
gtgcactccc ccggcgagca ctcggggcaa tcccagggcc caccgacccc acccaccacc 720
cccaaaaccg acgtgcagcc gggcaaggct gacctgaagc gagaggggcg ccccttgcca 780
gaggggggca gacagccccc tatcgacttc cgcgacgtgg acatcggcga gctgagcagc 840
gacgtcatct ccaacatcga gaccttcgat gtcaacgagt ttgaccagta cctgccgccc 900
aacggccacc cgggggtgcc ggccacgcac ggccaggtca cctacacggg cagctacggc 960
atcagcagca ccgcggccac cccggcgagc gcgggccacg tgtggatgtc caagcagcag 1020
gcgccgccgc cacccccgca gcagccccca caggccccgc cggccccgca ggcgcccccg 1080
cagccgcagg cggcgccccc acagcagccg gcggcacccc cgcagcagcc acaggcgcac 1140
acgctgacca cgctgagcag cgagccgggc cagtcccagc gaacgcacat caagacggag 1200
cagctgagcc ccagccacta cagcgagcag cagcagcact cgccccaaca gatcgcctac 1260
agccccttca acctcccaca ctacagcccc tcctacccgc ccatcacccg ctcacagtac 1320
gactacaccg accaccagaa ctccagctcc tactacagcc acgcggcagg ccagggcacc 1380
ggcctctact ccaccttcac ctacatgaac cccgctcagc gccccatgta cacccccatc 1440
gccgacacct ctggggtccc ttccatcccg cagacccaca gcccccagca ctgggaacaa 1500
cccgtctaca cacagctcac tcgaccttga 1530
<210> 79
<211> 807
<212> DNA
<213> 人类
<400> 79
atgccgcgct ccttcctggt caagaagcat ttcaacgcct ccaaaaagcc aaactacagc 60
gaactggaca cacatacagt gattatttcc ccgtatctct atgagagtta ctccatgcct 120
gtcataccac aaccagagat cctcagctca ggagcataca gccccatcac tgtgtggact 180
accgctgctc cattccacgc ccagctaccc aatggcctct ctcctctttc cggatactcc 240
tcatctttgg ggcgagtgag tccccctcct ccatctgaca cctcctccaa ggaccacagt 300
ggctcagaaa gccccattag tgatgaagag gaaagactac agtccaagct ttcagacccc 360
catgccattg aagctgaaaa gtttcagtgc aatttatgca ataagaccta ttcaactttt 420
tctgggctgg ccaaacataa gcagctgcac tgcgatgccc agtctagaaa atctttcagc 480
tgtaaatact gtgacaagga atatgtgagc ctgggcgccc tgaagatgca tattcggacc 540
cacacattac cttgtgtttg caagatctgc ggcaaggcgt tttccagacc ctggttgctt 600
caaggacaca ttagaactca cacgggggag aagccttttt cttgccctca ctgcaacaga 660
gcatttgcag acaggtcaaa tctgagggct catctgcaga cccattctga tgtaaagaaa 720
taccagtgca aaaactgctc caaaaccttc tccagaatgt ctctcctgca caaacatgag 780
gaatctggct gctgtgtagc acactga 807
<210> 80
<211> 1062
<212> DNA
<213> 人类
<400> 80
atggccgcgg agctggcgat gggcgccgag ctgcccagca gcccgctggc catcgagtac 60
gtcaacgact tcgacctgat gaagttcgag gtgaagaagg agcctcccga ggccgagcgc 120
ttctgccacc gcctgccgcc aggctcgctg tcctcgacgc cgctcagcac gccctgctcc 180
tccgtgccct cctcgcccag cttctgcgcg cccagcccgg gcaccggcgg cggcggcggc 240
gcggggggcg gcggcggctc gtctcaggcc gggggcgccc ccgggccgcc gagcgggggc 300
cccggcgccg tcgggggcac ctcggggaag ccggcgctgg aggatctgta ctggatgagc 360
ggctaccagc atcacctcaa ccccgaggcg ctcaacctga cgcccgagga cgcggtggag 420
gcgctcatcg gcagcggcca ccacggcgcg caccacggcg cgcaccaccc ggcggccgcc 480
gcagcctacg aggctttccg cggcccgggc ttcgcgggcg gcggcggagc ggacgacatg 540
ggcgccggcc accaccacgg cgcgcaccac gccgcccacc atcaccacgc cgcccaccac 600
caccaccacc accaccacca ccatggcggc gcgggacacg gcggtggcgc gggccaccac 660
gtgcgcctgg aggagcgctt ctccgacgac cagctggtgt ccatgtcggt gcgcgagctg 720
aaccggcagc tccgcggctt cagcaaggag gaggtcatcc ggctcaagca gaagcggcgc 780
acgctcaaga accgcggcta cgcgcagtcc tgccgcttca agcgggtgca gcagcggcac 840
attctggaga gcgagaagtg ccaactccag agccaggtgg agcagctgaa gctggaggtg 900
gggcgcctgg ccaaagagcg ggacctgtac aaggagaaat acgagaagct ggcgggccgg 960
ggcggccccg ggagcgcggg cggggccggt ttcccgcggg agccttcgcc gccgcaggcc 1020
ggtcccggcg gggccaaggg cacggccgac ttcttcctgt ag 1062
<210> 81
<211> 1071
<212> DNA
<213> 人类
<400> 81
atgaccaaat cgtacagcga gagtgggctg atgggcgagc ctcagcccca aggtcctcca 60
agctggacag acgagtgtct cagttctcag gacgaggagc acgaggcaga caagaaggag 120
gacgacctcg aagccatgaa cgcagaggag gactcactga ggaacggggg agaggaggag 180
gacgaagatg aggacctgga agaggaggaa gaagaggaag aggaggatga cgatcaaaag 240
cccaagagac gcggccccaa aaagaagaag atgactaagg ctcgcctgga gcgttttaaa 300
ttgagacgca tgaaggctaa cgcccgggag cggaaccgca tgcacggact gaacgcggcg 360
ctagacaacc tgcgcaaggt ggtgccttgc tattctaaga cgcagaagct gtccaaaatc 420
gagactctgc gcttggccaa gaactacatc tgggctctgt cggagatcct gcgctcaggc 480
aaaagcccag acctggtctc cttcgttcag acgctttgca agggcttatc ccaacccacc 540
accaacctgg ttgcgggctg cctgcaactc aatcctcgga cttttctgcc tgagcagaac 600
caggacatgc ccccccacct gccgacggcc agcgcttcct tccctgtaca cccctactcc 660
taccagtcgc ctgggctgcc cagtccgcct tacggtacca tggacagctc ccatgtcttc 720
cacgttaagc ctccgccgca cgcctacagc gcagcgctgg agcccttctt tgaaagccct 780
ctgactgatt gcaccagccc ttcctttgat ggacccctca gcccgccgct cagcatcaat 840
ggcaacttct ctttcaaaca cgaaccgtcc gccgagtttg agaaaaatta tgcctttacc 900
atgcactatc ctgcagcgac actggcaggg gcccaaagcc acggatcaat cttctcaggc 960
accgctgccc ctcgctgcga gatccccata gacaatatta tgtccttcga tagccattca 1020
catcatgagc gagtcatgag tgcccagctc aatgccatat ttcatgatta g 1071
<210> 82
<211> 768
<212> DNA
<213> 人类
<400> 82
atggacgtga tggatggctg ccagttctca ccttctgagt acttctacga cggctcctgc 60
ataccgtccc ccgagggtga atttggggac gagtttgtgc cgcgagtggc tgccttcgga 120
gcgcacaaag cagagctgca gggctcagat gaggacgagc acgtgcgagc gcctaccggc 180
caccaccagg ctggtcactg cctcatgtgg gcctgcaaag cctgcaagag gaagtccacc 240
accatggatc ggcggaaggc agccactatg cgcgagcgga ggcgcctgaa gaaggtcaac 300
caggctttcg aaaccctcaa gaggtgtacc acgaccaacc ccaaccagag gctgcccaag 360
gtggagatcc tcaggaatgc catccgctac atcgagagcc tgcaggagtt gctgagagag 420
caggtggaga actactatag cctgccggga cagagctgct cggagcccac cagccccacc 480
tccaactgct ctgatggcat gcccgaatgt aacagtcctg tctggtccag aaagagcagt 540
acttttgaca gcatctactg tcctgatgta tcaaatgtat atgccacaga taaaaactcc 600
ttatccagct tggattgctt atccaacata gtggaccgga tcacctcctc agagcaacct 660
gggttgcctc tccaggatct ggcttctctc tctccagttg ccagcaccga ttcacagcct 720
gcaactccag gggcttctag ttccaggctt atctatcatg tgctatga 768
<210> 83
<211> 3831
<212> DNA
<213> 人类
<400> 83
atgcgatcca aggcgagggc gaggaagcta gccaaaagtg acggtgacgt tgtaaataat 60
atgtatgagc ccaaccggga cctgctggcc agccacagcg cggaggacga ggccgaggac 120
agtgccatgt cgcccatccc cgtggggtca ccgcccccct tccccaccag cgaggacttc 180
acccccaagg agggctcgcc gtacgaggcc cctgtctaca ttcctgaaga cattccgatc 240
ccagcagact tcgagctccg agagtcctcc atcccagggg ctggcctggg ggtctgggcc 300
aagaggaaga tggaagccgg ggagaggctg ggcccctgcg tggtggtgcc ccgggcggcg 360
gcaaaggaga cagacttcgg atgggagcaa atactgacgg acgtggaagt gtcgccccag 420
gaaggctgca tcacaaagat ctccgaagac ctgggcagtg agaagttctg cgtggatgca 480
aatcaggcgg gggctggcag ctggctcaag tacatccgtg tggcgtgctc ctgcgatgac 540
cagaacctca ccatgtgtca gatcagtgag caggtaattt actataaagt cattaaggac 600
attgagccag gtgaggagct gctggtgcac gtgaaggaag gcgtctaccc cctgggcaca 660
gtgccgcccg gcctggacga ggagcccacg ttccgctgtg acgagtgtga cgaactcttc 720
cagtccaagc tggacctgcg gcgccataag aagtacacgt gtggctcagt gggggctgcg 780
ctctacgagg gcctggctga ggagctcaag cccgagggcc ttggcggtgg cagcggccaa 840
gcccacgagt gcaaggactg cgagcggatg ttccccaaca agtacagcct ggagcagcac 900
atggtcatcc acacggagga gcgcgagtac aaatgcgacc agtgtcccaa ggccttcaac 960
tggaagtcca acttcatccg ccaccagatg tcccacgaca gcggcaaacg cttcgaatgt 1020
gaaaactgcg tgaaggtgtt cacggacccc agcaaccttc agcggcacat ccgctcgcag 1080
cacgtgggcg ctcgggccca cgcctgcccc gactgcggga agaccttcgc cacgtcctcc 1140
ggcctcaagc agcacaagca tatccacagc acggtgaagc ctttcatatg tgaggtctgc 1200
cacaagtcct acacgcagtt ctccaacctg tgccggcaca agcggatgca cgccgactgc 1260
cgcacgcaga tcaagtgcaa ggactgtggc cagatgttca gcactacctc ctccctcaac 1320
aagcaccggc gcttctgcga gggcaagaac cattacacgc cgggcggcat ctttgccccg 1380
ggcctgccct tgacccccag ccccatgatg gacaaggcaa aaccctcccc cagcctcaat 1440
cacgccagcc tgggcttcaa cgagtacttt ccctacaggc cgcacccggg gagcctgccc 1500
ttctccacgg cgcctcccac gttccccgca ctcacccccg gcttcccggg catcttccct 1560
ccatccttgt acccccggcc gcctctgcta cctcccacat cgctgctcaa gagccccctg 1620
aaccacaccc aggacgccaa gctccccagt cccctgggga acccagccct gcccctggtc 1680
tccgccgtca gcaacagcag ccagggcacg acggcagctg cggggcccga ggagaagttc 1740
gagagccgcc tggaggactc ctgtgtggag aagctgaaga ccaggagcag cgacatgtcg 1800
gacggcagtg actttgagga cgtcaacacc accacgggga ccgacctgga cacgaccacg 1860
gggacgggct cggacctgga cagcgacgtg gacagcgacc ctgacaagga caagggcaag 1920
ggcaagtccg ccgagggcca gcccaagttt gggggcggct tggcgccccc gggggccccg 1980
aacagcgtgg ccgaggtgcc tgtcttctat tcccagcact cattcttccc gccacccgac 2040
gagcagctgc tgactgcaac gggcgccgcc ggggactcca tcaaggccat cgcatccatt 2100
gccgagaagt actttggccc cggcttcatg gggatgcagg agaagaagct gggctcgctc 2160
ccctaccact cggcgttccc cttccagttc ctgcccaact tcccccactc cctttacccc 2220
ttcacggacc gagccctcgc ccacaacttg ctggtcaagg ccgagccaaa gtcaccccgg 2280
gacgccctca aggtgggcgg ccccagtgcc gagtgcccct ttgatctcac caccaagccc 2340
aaagacgtga agcccatcct gcccatgccc aagggcccct cggcccccgc atccggcgag 2400
gagcagccgc tggacctgag catcggcagc cgggcccgtg ccagccaaaa cggcggcggg 2460
cgggagcccc gcaagaacca cgtctatggg gaacgcaagc tgggcgccgg cgaggggctg 2520
ccccaggtgt gcccggcgcg gatgccccag cagcccccgc tccactacgc caagccctcg 2580
cccttcttca tggaccccat ctacagggta gaaaagcgga aggtcacaga ccccgtggga 2640
gccctgaagg agaagtacct gcggccgtcc ccgctgctct tccaccccca gatgtcagcc 2700
atagagacca tgacagagaa gctggagagc tttgcagcca tgaaggcgga ctcgggcagc 2760
tccctgcagc ccctccccca ccaccccttc aacttccggt ccccaccccc aacgctctcc 2820
gaccccatcc tcaggaaggg caaggagcga tacacgtgca ggtactgtgg gaagatcttc 2880
cccagatcag ccaatctcac cagacacctg aggacgcaca ctggggagca gccgtacagg 2940
tgtaagtact gcgaccgctc cttcagcatc tcttcgaacc tccagcggca cgtccggaac 3000
atccacaaca aggagaagcc tttcaagtgc cacctgtgca accgctgctt cgggcagcag 3060
accaacctgg accggcacct caagaagcac gagcacgaga acgcaccagt gagccagcac 3120
cccggggtcc tcacgaacca cctggggacc agcgcgtcct ctcccacctc agagtcggac 3180
aaccacgcac ttttagacga gaaagaagac tcttatttct cggaaatcag aaactttatt 3240
gccaatagtg agatgaacca agcatcaacg cgaacagaga aacgggcgga catgcagatc 3300
gtggacggca gtgcccagtg tccaggccta gccagtgaga agcaggagga cgtggaggag 3360
gaggacgacg atgacctgga ggaggacgat gaggacagcc tggccgggaa gtcgcaggat 3420
gacaccgtgt cccccgcacc cgagccccag gccgcctacg aggatgagga ggatgaggag 3480
ccagccgcct ccctggccgt gggctttgac cacacccgaa ggtgtgctga ggaccacgaa 3540
ggcggtctgt tagctttgga gccgatgccg acttttggga aggggctgga cctccgcaga 3600
gcagctgagg aagcatttga agttaaagat gtgcttaatt ccaccttaga ttctgaggct 3660
ttaaaacata cactgtgcag gcaggctaag aaccaggcat atgcaatgat gctgtccctt 3720
tccgaagaca ctcctctcca caccccctcc cagggttctc tggacgcttg gttgaaggtc 3780
actggagcca cgtcggagtc tggagcattt caccccatca accacctctg a 3831
<210> 84
<211> 1311
<212> DNA
<213> 人类
<400> 84
atgcagaaca gtcacagcgg agtgaatcag ctcggtggtg tctttgtcaa cgggcggcca 60
ctgccggact ccacccggca gaagattgta gagctagctc acagcggggc ccggccgtgc 120
gacatttccc gaattctgca gacccatgca gatgcaaaag tccaagtgct ggacaatcaa 180
aacgtgtcca acggatgtgt gagtaaaatt ctgggcaggt attacgagac tggctccatc 240
agacccaggg caatcggtgg tagtaaaccg agagtagcga ctccagaagt tgtaagcaaa 300
atagcccagt ataagcggga gtgcccgtcc atctttgctt gggaaatccg agacagatta 360
ctgtccgagg gggtctgtac caacgataac ataccaagcg tgtcatcaat aaacagagtt 420
cttcgcaacc tggctagcga aaagcaacag atgggcgcag acggcatgta tgataaacta 480
aggatgttga acgggcagac cggaagctgg ggcacccgcc ctggttggta tccggggact 540
tcggtgccag ggcaacctac gcaagatggc tgccagcaac aggaaggagg gggagagaat 600
accaactcca tcagttccaa cggagaagat tcagatgagg ctcaaatgcg acttcagctg 660
aagcggaagc tgcaaagaaa tagaacatcc tttacccaag agcaaattga ggccctggag 720
aaagagtttg agagaaccca ttatccagat gtgtttgccc gagaaagact agcagccaaa 780
atagatctac ctgaagcaag aatacaggta tggttttcta atcgaagggc caaatggaga 840
agagaagaaa aactgaggaa tcagagaaga caggccagca acacacctag tcatattcct 900
atcagcagta gtttcagcac cagtgtctac caaccaattc cacaacccac cacaccggtt 960
tcctccttca catctggctc catgttgggc cgaacagaca cagccctcac aaacacctac 1020
agcgctctgc cgcctatgcc cagcttcacc atggcaaata acctgcctat gcaaccccca 1080
gtccccagcc agacctcctc atactcctgc atgctgccca ccagcccttc ggtgaatggg 1140
cggagttatg atacctacac ccccccacat atgcagacac acatgaacag tcagccaatg 1200
ggcacctcgg gcaccacttc aacaggactc atttcccctg gtgtgtcagt tccagttcaa 1260
gttcccggaa gtgaacctga tatgtctcaa tactggccaa gattacagta a 1311
<210> 85
<211> 1896
<212> DNA
<213> 人类
<400> 85
atggtttcta aactgagcca gctgcagacg gagctcctgg cggccctgct cgagtcaggg 60
ctgagcaaag aggcactgat ccaggcactg ggtgagccgg ggccctacct cctggctgga 120
gaaggccccc tggacaaggg ggagtcctgc ggcggcggtc gaggggagct ggctgagctg 180
cccaatgggc tgggggagac tcggggctcc gaggacgaga cggacgacga tggggaagac 240
ttcacgccac ccatcctcaa agagctggag aacctcagcc ctgaggaggc ggcccaccag 300
aaagccgtgg tggagaccct tctgcaggag gacccgtggc gtgtggcgaa gatggtcaag 360
tcctacctgc agcagcacaa catcccacag cgggaggtgg tcgataccac tggcctcaac 420
cagtcccacc tgtcccaaca cctcaacaag ggcactccca tgaagacgca gaagcgggcc 480
gccctgtaca cctggtacgt ccgcaagcag cgagaggtgg cgcagcagtt cacccatgca 540
gggcagggag ggctgattga agagcccaca ggtgatgagc taccaaccaa gaaggggcgg 600
aggaaccgtt tcaagtgggg cccagcatcc cagcagatcc tgttccaggc ctatgagagg 660
cagaagaacc ctagcaagga ggagcgagag acgctagtgg aggagtgcaa tagggcggaa 720
tgcatccaga gaggggtgtc cccatcacag gcacaggggc tgggctccaa cctcgtcacg 780
gaggtgcgtg tctacaactg gtttgccaac cggcgcaaag aagaagcctt ccggcacaag 840
ctggccatgg acacgtacag cgggcccccc ccagggccag gcccgggacc tgcgctgccc 900
gctcacagct cccctggcct gcctccacct gccctctccc ccagtaaggt ccacggtgtg 960
cgctatggac agcctgcgac cagtgagact gcagaagtac cctcaagcag cggcggtccc 1020
ttagtgacag tgtctacacc cctccaccaa gtgtccccca cgggcctgga gcccagccac 1080
agcctgctga gtacagaagc caagctggtc tcagcagctg ggggccccct cccccctgtc 1140
agcaccctga cagcactgca cagcttggag cagacatccc caggcctcaa ccagcagccc 1200
cagaacctca tcatggcctc acttcctggg gtcatgacca tcgggcctgg tgagcctgcc 1260
tccctgggtc ctacgttcac caacacaggt gcctccaccc tggtcatcgg cctggcctcc 1320
acgcaggcac agagtgtgcc ggtcatcaac agcatgggca gcagcctgac caccctgcag 1380
cccgtccagt tctcccagcc gctgcacccc tcctaccagc agccgctcat gccacctgtg 1440
cagagccatg tgacccagag ccccttcatg gccaccatgg ctcagctgca gagcccccac 1500
gccctctaca gccacaagcc cgaggtggcc cagtacaccc acacgggcct gctcccgcag 1560
actatgctca tcaccgacac caccaacctg agcgccctgg ccagcctcac gcccaccaag 1620
caggtcttca cctcagacac tgaggcctcc agtgagtccg ggcttcacac gccggcatct 1680
caggccacca ccctccacgt ccccagccag gaccctgccg gcatccagca cctgcagccg 1740
gcccaccggc tcagcgccag ccccacagtg tcctccagca gcctggtgct gtaccagagc 1800
tcagactcca gcaatggcca gagccacctg ctgccatcca accacagcgt catcgagacc 1860
ttcatctcca cccagatggc ctcttcctcc cagtaa 1896
<210> 86
<211> 1053
<212> DNA
<213> 人类
<400> 86
atgctgggct cagtgaagat ggaggcccat gacctggccg agtggagcta ctacccggag 60
gcgggcgagg tctactcgcc ggtgacccca gtgcccacca tggcccccct caactcctac 120
atgaccctga atcctctaag ctctccctat ccccctgggg ggctccctgc ctccccactg 180
ccctcaggac ccctggcacc cccagcacct gcagcccccc tggggcccac tttcccaggc 240
ctgggtgtca gcggtggcag cagcagctcc gggtacgggg ccccgggtcc tgggctggtg 300
cacgggaagg agatgccgaa ggggtatcgg cggcccctgg cacacgccaa gccaccgtat 360
tcctatatct cactcatcac catggccatc cagcaggcgc cgggcaagat gctgaccttg 420
agtgaaatct accagtggat catggacctc ttcccttact accgggagaa tcagcagcgc 480
tggcagaact ccattcgcca ctcgctgtct ttcaacgact gcttcgtcaa ggtggcgcgt 540
tccccagaca agcctggcaa gggctcctac tgggccctac accccagctc agggaacatg 600
tttgagaatg gctgctacct gcgccgccag aaacgcttca agctggagga gaaggtgaaa 660
aaagggggca gcggggctgc caccaccacc aggaacggga cagggtctgc tgcctcgacc 720
accacccccg cggccacagt cacctccccg ccccagcccc cgcctccagc ccctgagcct 780
gaggcccagg gcggggaaga tgtgggggct ctggactgtg gctcacccgc ttcctccaca 840
ccctatttca ctggcctgga gctcccaggg gagctgaagc tggacgcgcc ctacaacttc 900
aaccaccctt tctccatcaa caacctaatg tcagaacaga caccagcacc tcccaaactg 960
gacgtggggt ttgggggcta cggggctgaa ggtggggagc ctggagtcta ctaccagggc 1020
ctctattccc gctctttgct taatgcatcc tag 1053
<210> 87
<211> 1053
<212> DNA
<213> 人类
<400> 87
atgctgggct cagtgaagat ggaggcccat gacctggccg agtggagcta ctacccggag 60
gcgggcgagg tctactcgcc ggtgacccca gtgcccacca tggcccccct caactcctac 120
atgaccctga atcctctaag ctctccctat ccccctgggg ggctccctgc ctccccactg 180
ccctcaggac ccctggcacc cccagcacct gcagcccccc tggggcccac tttcccaggc 240
ctgggtgtca gcggtggcag cagcagctcc gggtacgggg ccccgggtcc tgggctggtg 300
cacgggaagg agatgccgaa ggggtatcgg cggcccctgg cacacgccaa gccaccgtat 360
tcctatatct cactcatcac catggccatc cagcaggcgc cgggcaagat gctgaccttg 420
agtgaaatct accagtggat catggacctc ttcccttact accgggagaa tcagcagcgc 480
tggcagaact ccattcgcca ctcgctgtct ttcaacgact gcttcgtcaa ggtggcgcgt 540
tccccagaca agcctggcaa gggctcctac tgggccctac accccagctc agggaacatg 600
tttgagaatg gctgctacct gcgccgccag aaacgcttca agctggagga gaaggtgaaa 660
aaagggggca gcggggctgc caccaccacc aggaacggga cagggtctgc tgcctcgacc 720
accacccccg cggccacagt cacctccccg ccccagcccc cgcctccagc ccctgagcct 780
gaggcccagg gcggggaaga tgtgggggct ctggactgtg gctcacccgc ttcctccaca 840
ccctatttca ctggcctgga gctcccaggg gagctgaagc tggacgcgcc ctacaacttc 900
aaccaccctt tctccatcaa caacctaatg tcagaacaga caccagcacc tcccaaactg 960
gacgtggggt ttgggggcta cggggctgaa ggtggggagc ctggagtcta ctaccagggc 1020
ctctattccc gctctttgct taatgcatcc tag 1053
<210> 88
<211> 1392
<212> DNA
<213> 人类
<400> 88
atgcactcgg cttccagtat gctgggagcg gtgaagatgg aagggcacga gccgtccgac 60
tggagcagct actatgcaga gcccgagggc tactcctccg tgagcaacat gaacgccggc 120
ctggggatga acggcatgaa cacgtacatg agcatgtcgg cggccgccat gggcagcggc 180
tcgggcaaca tgagcgcggg ctccatgaac atgtcgtcgt acgtgggcgc tggcatgagc 240
ccgtccctgg cggggatgtc ccccggcgcg ggcgccatgg cgggcatggg cggctcggcc 300
ggggcggccg gcgtggcggg catggggccg cacttgagtc ccagcctgag cccgctcggg 360
gggcaggcgg ccggggccat gggcggcctg gccccctacg ccaacatgaa ctccatgagc 420
cccatgtacg ggcaggcggg cctgagccgc gcccgcgacc ccaagaccta caggcgcagc 480
tacacgcacg caaagccgcc ctactcgtac atctcgctca tcaccatggc catccagcag 540
agccccaaca agatgctgac gctgagcgag atctaccagt ggatcatgga cctcttcccc 600
ttctaccggc agaaccagca gcgctggcag aactccatcc gccactcgct ctccttcaac 660
gactgtttcc tgaaggtgcc ccgctcgccc gacaagcccg gcaagggctc cttctggacc 720
ctgcaccctg actcgggcaa catgttcgag aacggctgct acctgcgccg ccagaagcgc 780
ttcaagtgcg agaagcagct ggcgctgaag gaggccgcag gcgccgccgg cagcggcaag 840
aaggcggccg ccggagccca ggcctcacag gctcaactcg gggaggccgc cgggccggcc 900
tccgagactc cggcgggcac cgagtcgcct cactcgagcg cctccccgtg ccaggagcac 960
aagcgagggg gcctgggaga gctgaagggg acgccggctg cggcgctgag ccccccagag 1020
ccggcgccct ctcccgggca gcagcagcag gccgcggccc acctgctggg cccgccccac 1080
cacccgggcc tgccgcctga ggcccacctg aagccggaac accactacgc cttcaaccac 1140
ccgttctcca tcaacaacct catgtcctcg gagcagcagc accaccacag ccaccaccac 1200
caccaacccc acaaaatgga cctcaaggcc tacgaacagg tgatgcacta ccccggctac 1260
ggttccccca tgcctggcag cttggccatg ggcccggtca cgaacaaaac gggcctggac 1320
gcctcgcccc tggccgcaga tacctcctac taccaggggg tgtactcccg gcccattatg 1380
aactcctctt aa 1392
<210> 89
<211> 1035
<212> DNA
<213> 人类
<400> 89
atgagcagcc acctgcagag ccccccgcac gcgcccagca gcgccgcctt cggctttccc 60
cggggcgcgg gccccgcgca gcctcccgcc ccacctgccg ccccggagcc gctgggcggc 120
atctgcgagc acgagacgtc catcgacatc agcgcctaca tcgacccggc cgccttcaac 180
gacgagttcc tggccgacct gttccagcac agccggcagc aggagaaggc caaggcggcc 240
gtgggcccca cgggcggcgg cggcggcggc gactttgact acccgggcgc gcccgcgggc 300
cccggcggcg ccgtcatgcc cgggggagcg cacgggcccc cgcccggcta cggctgcgcg 360
gccgccggct acctggacgg caggctggag cccctgtacg agcgcgtcgg ggcgccggcg 420
ctgcggccgc tggtgatcaa gcaggagccc cgcgaggagg atgaagccaa gcagctggcg 480
ctggccggcc tcttccctta ccagccgccg ccgccgccgc cgccctcgca cccgcacccg 540
cacccgccgc ccgcgcacct ggccgccccg cacctgcagt tccagatcgc gcactgcggc 600
cagaccacca tgcacctgca gcccggtcac cccacgccgc cgcccacgcc cgtgcccagc 660
ccgcaccccg cgcccgcgct cggtgccgcc ggcctgccgg gccctggcag cgcgctcaag 720
gggctgggcg ccgcgcaccc cgacctccgc gcgagtggcg gcagcggcgc gggcaaggcc 780
aagaagtcgg tggacaagaa cagcaacgag taccgggtgc ggcgcgagcg caacaacatc 840
gcggtgcgca agagccgcga caaggccaag cagcgcaacg tggagacgca gcagaaggtg 900
ctggagctga ccagtgacaa tgaccgcctg cgcaagcggg tggaacagct gagccgcgaa 960
ctggacacgc tgcggggcat cttccgccag ctgccagaga gctccttggt caaggccatg 1020
ggcaactgcg cgtga 1035
<210> 90
<211> 816
<212> DNA
<213> 人类
<400> 90
atgttacagg cgtgcaaaat ggaagggttt cccctcgtcc cccctcagcc atcagaagac 60
ctggtgccct atgacacgga tctataccaa cgccaaacgc acgagtatta cccctatctc 120
agcagtgatg gggagagcca tagcgaccat tactgggact tccaccccca ccacgtgcac 180
agcgagttcg agagcttcgc cgagaacaac ttcacggagc tccagagcgt gcagcccccg 240
cagctgcagc agctctaccg ccacatggag ctggagcaga tgcacgtcct cgataccccc 300
atggtgccac cccatcccag tcttggccac caggtctcct acctgccccg gatgtgcctc 360
cagtacccat ccctgtcccc agcccagccc agctcagatg aggaggaggg cgagcggcag 420
agccccccac tggaggtgtc tgacggcgag gcggatggcc tggagcccgg gcctgggctc 480
ctgcctgggg agacaggcag caagaagaag atccgcctgt accagttcct gttggacctg 540
ctccgcagcg gcgacatgaa ggacagcatc tggtgggtgg acaaggacaa gggcaccttc 600
cagttctcgt ccaagcacaa ggaggcgctg gcgcaccgct ggggcatcca gaagggcaac 660
cgcaagaaga tgacctacca gaagatggcg cgcgcgctgc gcaactacgg caagacgggc 720
gaggtcaaga aggtgaagaa gaagctcacc taccagttca gcggcgaagt gctgggccgc 780
gggggcctgg ccgagcggcg ccacccgccc cactga 816
<210> 91
<211> 1332
<212> DNA
<213> 人类
<400> 91
atggcgaccg cagcgtctaa ccactacagc ctgctcacct ccagcgcctc catcgtgcac 60
gccgagccgc ccggcggcat gcagcagggc gcggggggct accgcgaagc gcagagcctg 120
gtgcagggcg actacggcgc tctgcagagc aacggacacc cgctcagcca cgctcaccag 180
tggatcaccg cgctgtccca cggcggcggc ggcgggggcg gtggcggcgg cggggggggc 240
gggggcggcg gcgggggcgg cggcgacggc tccccgtggt ccaccagccc cctgggccag 300
ccggacatca agccctcggt ggtggtgcag cagggcggcc gcggagacga gctgcacggg 360
ccaggcgccc tgcagcagca gcatcagcag cagcaacagc aacagcagca gcaacagcag 420
caacagcagc agcagcagca gcaacagcgg ccgccgcatc tggtgcacca cgccgctaac 480
caccacccgg gacccggggc atggcggagc gcggcggctg cagcgcacct cccaccctcc 540
atgggagcgt ccaacggcgg cttgctctac tcgcagccca gcttcacggt gaacggcatg 600
ctgggcgccg gcgggcagcc ggccggtctg caccaccacg gcctgcggga cgcgcacgac 660
gagccacacc atgccgacca ccacccgcac ccgcactcgc acccacacca gcagccgccg 720
cccccgccgc ccccgcaggg tccgcctggc cacccaggcg cgcaccacga cccgcactcg 780
gacgaggaca cgccgacctc ggacgacctg gagcagttcg ccaagcagtt caagcagcgg 840
cggatcaaac tgggatttac ccaagcggac gtggggctgg ctctgggcac cctgtatggc 900
aacgtgttct cgcagaccac catctgcagg tttgaggccc tgcagctgag cttcaagaac 960
atgtgcaagc tgaagccttt gttgaacaag tggttggagg aggcggactc gtcctcgggc 1020
agccccacga gcatagacaa gatcgcagcg caagggcgca agcggaaaaa gcggacctcc 1080
atcgaggtga gcgtcaaggg ggctctggag agccatttcc tcaaatgccc caagccctcg 1140
gcccaggaga tcacctccct cgcggacagc ttacagctgg agaaggaggt ggtgagagtt 1200
tggttttgta acaggagaca gaaagagaaa aggatgaccc ctcccggagg gactctgccg 1260
ggcgccgagg atgtgtacgg ggggagtagg gacactccac cacaccacgg ggtgcagacg 1320
cccgtccagt ga 1332
<210> 92
<211> 1470
<212> DNA
<213> 人类
<400> 92
atgctggaca tgggagatag gaaagaggtg aaaatgatcc ccaagtcctc gttcagcatc 60
aacagcctgg tgcccgaggc ggtccagaac gacaaccacc acgcgagcca cggccaccac 120
aacagccacc acccccagca ccaccaccac caccaccacc atcaccacca cccgccgccg 180
cccgccccgc aaccgccgcc gccgccgcag cagcagcagc cgccgccgcc gccgcccccg 240
gcaccgcagc ccccccagac gcggggcgcc ccggccgccg acgacgacaa gggcccccag 300
cagctgctgc tcccgccgcc gccaccgcca ccaccggccg ccgccctgga cggggctaaa 360
gcggacgggc tgggcggcaa gggcgagccg ggcggcgggc cgggggagct ggcgcccgtc 420
gggccggacg agaaggagaa gggcgccggc gccggggggg aggagaagaa gggggcgggc 480
gagggcggca aggacgggga ggggggcaag gagggcgaga agaagaacgg caagtacgag 540
aagccgccgt tcagctacaa cgcgctcatc atgatggcca tccggcagag ccccgagaag 600
cggctcacgc tcaacggcat ctacgagttc atcatgaaga acttccctta ctaccgcgag 660
aacaagcagg gctggcagaa ctccatccgc cacaatctgt ccctcaacaa gtgcttcgtg 720
aaggtgccgc gccactacga cgacccgggc aagggcaact actggatgct ggacccgtcg 780
agcgacgacg tgttcatcgg cggcaccacg ggcaagctgc ggcgccgctc caccacctcg 840
cgggccaagc tggccttcaa gcgcggtgcg cgcctcacct ccaccggcct caccttcatg 900
gaccgcgccg gctccctcta ctggcccatg tcgcccttcc tgtccctgca ccacccccgc 960
gccagcagca ctttgagtta caacggcacc acgtcggcct accccagcca ccccatgccc 1020
tacagctccg tgttgactca gaactcgctg ggcaacaacc actccttctc caccgccaac 1080
ggcctgagcg tggaccggct ggtcaacggg gagatcccgt acgccacgca ccacctcacg 1140
gccgccgcgc tagccgcctc ggtgccctgc ggcctgtcgg tgccctgctc tgggacctac 1200
tccctcaacc cctgctccgt caacctgctc gcgggccaga ccagttactt tttcccccac 1260
gtcccgcacc cgtcaatgac ttcgcagagc agcacgtcca tgagcgccag ggccgcgtcc 1320
tcctccacgt cgccgcaggc cccctcgacc ctgccctgtg agtctttaag accctctttg 1380
ccaagtttta cgacgggact gtctggggga ctgtctgatt atttcacaca tcaaaatcag 1440
gggtcttctt ccaacccttt aatacattaa 1470
<210> 93
<211> 1572
<212> DNA
<213> 人类
<400> 93
atggccggcc acacgcagca gccgagcggg cgcgggaacc ccaggcctgc gccctcgccc 60
tccccagtcc cagggaccgt ccccggcgcc tcggagcggg tggcgctcaa gaaggagatc 120
gggctgctga gcgcctgcac catcatcatc gggaacatca tcggctcggg catcttcatc 180
tcgcccaagg gggtcctgga gcactcaggc tccgtgggtc tggccctgtt cgtctgggtc 240
ctgggtgggg gcgtgacggc tctgggctcc ctctgctatg cagagctggg agtcgccatc 300
cccaagtctg gcggggacta cgcctacgtc acagagatct tcgggggcct ggctggcttt 360
ctgctgctct ggagcgccgt cctcatcatg taccccacca gccttgctgt catctccatg 420
accttctcca actacgtgct gcagcccgtg ttccccaact gcatcccccc caccacagcc 480
tcccgggtgc tgtccatggc ctgcctgatg ctcctgacat gggtgaacag ctccagtgtg 540
cgctgggcca cgcgcatcca ggacatgttc acaggcggga agctgctggc cttgtccctc 600
atcatcggcg tgggccttct ccagatcttc caaggacact tcgaggagct gaggcccagc 660
aatgcctttg ctttctggat gacgccctcc gtgggacacc tggccctggc cttcctccag 720
ggctccttcg ccttcagtgg ctggaacttc ctcaactatg tcaccgagga gatggttgac 780
gcccgaaaga acctacctcg cgccatcttc atctccatcc cactggtgac cttcgtgtac 840
acgttcacca acattgccta cttcacggcc atgtcccccc aggagctgct ctcctccaat 900
gcggtggctg tgaccttcgg ggagaagctg ctgggctact tttcttgggt catgcctgtc 960
tccgtggctc tgtcaacctt cggagggatc aatggttacc tgttcaccta ctccaggctg 1020
tgcttctctg gagcccgcga ggggcacctg cccagcctgc tggccatgat ccacgtcaga 1080
cactgcaccc ccatccccgc cctcctcgtc tgttgcgggg ccacagccgt catcatgctc 1140
gtgggcgaca cgtacacgct catcaactat gtgtccttca tcaactacct ctgctacggc 1200
gtcaccatcc tgggcctgct gctgctgcgc tggaggcggc ctgcactcca caggcccatc 1260
aaggtgaacc ttctcatccc cgtggcgtac ttggtcttct gggccttcct gctggtcttc 1320
agcttcatct cagagcctat ggtctgtggg gtcggcgtca tcatcatcct tacgggggtg 1380
cccattttct ttctgggagt gttctggaga agcaaaccaa agtgtgtgca cagactcaca 1440
gagtccatga cacactgggg ccaggagctg tgtttcgtgg tctaccccca ggacgccccc 1500
gaagaggagg agaatggccc ctgcccaccc tccctgctgc ctgccacaga caagccctcg 1560
aagccacaat ga 1572
<210> 94
<211> 711
<212> DNA
<213> 人类
<400> 94
atggaaagct ctgccaagat ggagagcggc ggcgccggcc agcagcccca gccgcagccc 60
cagcagccct tcctgccgcc cgcagcctgt ttctttgcca cggccgcagc cgcggcggcc 120
gcagccgccg cagcggcagc gcagagcgcg cagcagcagc agcagcagca gcagcagcag 180
cagcaggcgc cgcagctgag accggcggcc gacggccagc cctcaggggg cggtcacaag 240
tcagcgccca agcaagtcaa gcgacagcgc tcgtcttcgc ccgaactgat gcgctgcaaa 300
cgccggctca acttcagcgg ctttggctac agcctgccgc agcagcagcc ggccgccgtg 360
gcgcgccgca acgagcgcga gcgcaaccgc gtcaagttgg tcaacctggg ctttgccacc 420
cttcgggagc acgtccccaa cggcgcggcc aacaagaaga tgagtaaggt ggagacactg 480
cgctcggcgg tcgagtacat ccgcgcgctg cagcagctgc tggacgagca tgacgcggtg 540
agcgccgcct tccaggcagg cgtcctgtcg cccaccatct cccccaacta ctccaacgac 600
ttgaactcca tggccggctc gccggtctca tcctactcgt cggacgaggg ctcttacgac 660
ccgctcagcc ccgaggagca ggagcttctc gacttcacca actggttctg a 711
<210> 95
<211> 1797
<212> DNA
<213> 人类
<400> 95
atgccttgtg ttcaggcgca gtatgggtcc tcgcctcaag gagccagccc cgcttctcag 60
agctacagtt accactcttc gggagaatac agctccgatt tcttaactcc agagtttgtc 120
aagtttagca tggacctcac caacactgaa atcactgcca ccacttctct ccccagcttc 180
agtaccttta tggacaacta cagcacaggc tacgacgtca agccaccttg cttgtaccaa 240
atgcccctgt ccggacagca gtcctccatt aaggtagaag acattcagat gcacaactac 300
cagcaacaca gccacctgcc cccccagtct gaggagatga tgccgcactc cgggtcggtt 360
tactacaagc cctcctcgcc cccgacgccc accaccccgg gcttccaggt gcagcacagc 420
cccatgtggg acgacccggg atctctccac aacttccacc agaactacgt ggccactacg 480
cacatgatcg agcagaggaa aacgccagtc tcccgcctct ccctcttctc ctttaagcaa 540
tcgccccctg gcaccccggt gtctagttgc cagatgcgct tcgacgggcc cctgcacgtc 600
cccatgaacc cggagcccgc cggcagccac cacgtggtgg acgggcagac cttcgctgtg 660
cccaacccca ttcgcaagcc cgcgtccatg ggcttcccgg gcctgcagat cggccacgcg 720
tctcagctgc tcgacacgca ggtgccctca ccgccgtcgc ggggctcccc ctccaacgag 780
gggctgtgcg ctgtgtgtgg ggacaacgcg gcctgccaac actacggcgt gcgcacctgt 840
gagggctgca aaggcttctt taagcgcaca gtgcaaaaaa atgcaaaata cgtgtgttta 900
gcaaataaaa actgcccagt ggacaagcgt cgccggaatc gctgtcagta ctgccgattt 960
cagaagtgcc tggctgttgg gatggtcaaa gaagtggttc gcacagacag tttaaaaggc 1020
cggagaggtc gtttgccctc gaaaccgaag agcccacagg agccctctcc cccttcgccc 1080
ccggtgagtc tgatcagtgc cctcgtcagg gcccatgtcg actccaaccc ggctatgacc 1140
agcctggact attccaggtt ccaggcgaac cctgactatc aaatgagtgg agatgacacc 1200
cagcatatcc agcaattcta tgatctcctg actggctcca tggagatcat ccggggctgg 1260
gcagagaaga tccctggctt cgcagacctg cccaaagccg accaagacct gctttttgaa 1320
tcagctttct tagaactgtt tgtccttcga ttagcataca ggtccaaccc agtggagggt 1380
aaactcatct tttgcaatgg ggtggtcttg cacaggttgc aatgcgttcg tggctttggg 1440
gaatggattg attccattgt tgaattctcc tccaacttgc agaatatgaa catcgacatt 1500
tctgccttct cctgcattgc tgccctggct atggtcacag agagacacgg gctcaaggaa 1560
cccaagagag tggaagaact gcaaaacaag attgtaaatt gtctcaaaga ccacgtgact 1620
ttcaacaatg gggggttgaa ccgccccaat tatttgtcca aactgttggg gaagctccca 1680
gaacttcgta ccctttgcac acaggggcta cagcgcattt tctacctgaa attggaagac 1740
ttggtgccac cgccagcaat aattgacaaa cttttcctgg acactttacc tttctaa 1797
<210> 96
<211> 819
<212> DNA
<213> 人类
<400> 96
atgttcgtca aatccgagac cttggagttg aaggaggaag aggacgtgtt agtgctgctc 60
ggatcggcct cccccgcctt ggcggccctg accccgctgt catccagcgc cgacgaagaa 120
gaggaggagg agccgggcgc gtcaggcggg gcgcgtcggc agcgcggggc tgaggccggg 180
cagggggcgc ggggcggcgt ggctgcgggt gcggagggct gccggcccgc acggctgctg 240
ggtctggtac acgattgcaa acggcgccct tcccgggcgc gggccgtctc ccgaggcgcc 300
aagacggccg agacggtgca gcgcatcaag aagacccgta gactgaaggc caacaaccgc 360
gagcgaaacc gcatgcacaa cctcaacgcg gcactggacg cgctgcgcga ggtgctcccc 420
acgttccccg aggacgccaa gctcaccaag atcgagaccc tgcgcttcgc ccacaactac 480
atctgggcac tcaccgagac cctgcgcctg gcggatcact gcgggggcgg cggcgggggc 540
ctgccggggg cgctcttctc cgaggcagtg ttgctgagcc cgggaggagc cagcgccgcc 600
ctgagcagca gcggagacag cccctcgccc gcctccacgt ggagttgcac caacagcccc 660
gcgccgtcct cctccgtgtc ctccaattcc acctccccct acagctgcac tttatcgccc 720
gccagcccgg ccgggtcaga catggactat tggcagcccc cacctcccga caagcaccgc 780
tatgcacctc acctccccat agccagggat tgtatctag 819
<210> 97
<211> 1149
<212> DNA
<213> 人类
<400> 97
atgctggacg gcctaaagat ggaggagaac ttccaaagcg cgatcgacac ctcggcctcc 60
ttctcctcgc tgctgggcag agcggtgagc cccaagtctg tctgcgaggg ctgtcagcgg 120
gtcatcttgg acaggtttct gctgcggctc aacgacagct tctggcatga gcagtgcgtg 180
cagtgcgcct cctgcaaaga gcccctggag accacctgct tctaccggga caagaagctg 240
tactgcaagt atgactacga gaagctgttt gctgttaaat gtgggggctg cttcgaggcc 300
atcgctccca atgagtttgt tatgcgggcc cagaagagtg tataccacct gagctgcttc 360
tgctgctgtg tctgcgagcg acagcttcag aagggtgatg agtttgtcct gaaggagggg 420
cagctgctct gcaaagggga ctatgagaag gagcgggagc tgctcagcct ggtgagccca 480
gcagcctcag actcaggtaa aagtgatgat gaagaaagtc tctgcaagtc agcccatggg 540
gcagggaaag gaactgctga ggaaggcaag gaccataagc gccccaaacg tccgagaacc 600
atcttgacaa ctcaacagag gcgagcattc aaggcctcat ttgaagtatc ctccaagccc 660
tgcaggaagg tgagagagac tctggctgca gagacagggc tgagtgtccg tgtcgtccag 720
gtgtggttcc aaaaccagag agcgaagatg aagaagctgg ccaggcgaca gcagcagcag 780
cagcaagatc agcagaacac ccagaggctg agctctgctc agacaaacgg tggtgggagt 840
gctgggatgg aaggaatcat gaacccctac acggctctgc ccaccccaca gcagctcctg 900
gccatcgagc agagtgtcta cagctcagat cccttccgac agggtctcac cccaccccag 960
atgcctggag accacatgca cccttatggt gccgagcccc ttttccatga cctggatagc 1020
gacgacacct ccctcagtaa cctgggtgat tgtttcctag caacctcaga agctgggcct 1080
ctgcagtcca gagtgggaaa ccccattgac catctgtact ccatgcagaa ttcttacttc 1140
acatcttga 1149
<210> 98
<211> 694
<212> DNA
<213> 人类
<400> 98
atggaaaaat ccaaaaattt ccgcatcgag ccctgctggc ggtggacccc ccacgagccg 60
cctctcgcag agcgcgcgct ggccaaggtc acgtcgccgc ccgtgcccgc atctggcacc 120
ggaggtggcg gcggcggcgg cggggcgagc ggcgggacta gcggcagctg cagccccgcg 180
tcctcggagc cgccggctgc gcccgccgac cgcctgcgcg ccgagagccc gtcgccgccg 240
cgcctgctgg ccgcgcactg cgcgctgctg cccaagccgg gcttcctggg cgcgggcggc 300
ggcggcggcg gcacgggcgg cgggcacggg gggccccacc accacgcgca tccgggcgca 360
gcggccgctg ccgccgccgc cgccgccgcc gccgccgccg ccgctggggg cctggcgctg 420
gggctgcacc ctgggggcgc gcagggcggc gcgggcctcc cggcgcaggc ggcgctctac 480
ggccacccgg tctacggcta ctccgcggcg gcggcggcgg ctgcgctggc gggccagcac 540
ccggcgctct cctactcgta cccgcaggtg caaggcgcgc accccgcgca ccccgccgac 600
cccatcaagc tgggcgccgg caccttccag ctggaccagt ggctgcgcgc gtccaccgcg 660
ggcatgatcc tgcctaagat gcccgacttc aact 694
<210> 99
<211> 1194
<212> DNA
<213> 人类
<400> 99
atgctgctgg aaacggggct cgagcgcgac cgagcgaggc ccggggccgc cgccgtctgc 60
accttgggcg ggactcggga gatcccgctg tgcgctggct gtgaccagca catcctggac 120
cgcttcatcc tcaaggctct ggaccgccac tggcacagca agtgtctcaa gtgcagcgac 180
tgccacacgc cactggccga gcgctgcttc agccgagggg agagcgttta ctgcaaggac 240
gactttttca agcgcttcgg gaccaagtgc gccgcgtgcc agctgggcat cccgcccacg 300
caggtggtgc gccgcgccca ggacttcgtg taccacctgc actgctttgc ctgcgtcgtg 360
tgcaagcggc agctggccac gggcgacgag ttctacctca tggaggacag ccggctcgtg 420
tgcaaggcgg actacgaaac cgccaagcag cgagaggccg aggccacggc caagcggccg 480
cgcacgacca tcaccgccaa gcagctggag acgctgaaga gcgcttacaa cacctcgccc 540
aagccggcgc gccacgtgcg cgagcagctc tcgtccgaga cgggcctgga catgcgcgtg 600
gtgcaggttt ggttccagaa ccgccgggcc aaggagaaga ggctgaagaa ggacgccggc 660
cggcagcgct gggggcagta tttccgcaac atgaagcgct cccgcggcgg ctccaagtcg 720
gacaaggaca gcgttcagga ggggcaggac agcgacgctg aggtctcctt ccccgatgag 780
ccttccttgg cggaaatggg cccggccaat ggcctctacg ggagcttggg ggaacccacc 840
caggccttgg gccggccctc gggagccctg ggcaacttct ccctggagca tggaggcctg 900
gcaggcccag agcagtaccg agagctgcgt cccggcagcc cctacggtgt ccccccatcc 960
cccgccgccc cgcagagcct ccctggcccc cagcccctcc tctccagcct ggtgtaccca 1020
gacaccagct tgggccttgt gccctcggga gcccccggcg ggcccccacc catgagggtg 1080
ctggcaggga acggacccag ttctgaccta tccacgggga gcagcggggg ttaccccgac 1140
ttccctgcca gccccgcctc ctggctggat gaggtagacc acgctcagtt ctga 1194
<210> 100
<211> 987
<212> DNA
<213> 人类
<400> 100
atgactggag tctttgacag tctagtggct gatatgcact cgacccagat cgccgcctcc 60
agcacgtacc accagcacca gcagcccccg agcggcggcg gcgccggccc gggtggcaac 120
agcagcagca gcagcagcct ccacaagccc caggagtcgc ccacccttcc ggtgtccacc 180
gccaccgaca gcagctacta caccaaccag cagcacccgg cgggcggcgg cggcggcggg 240
ggctcgccct acgcgcacat gggttcctac cagtaccaag ccagcggcct caacaacgtc 300
ccttactccg ccaagagcag ctatgacctg ggctacaccg ccgcctacac ctcctacgct 360
ccctatggaa ccagttcgtc cccagccaac aacgagcctg agaaggagga ccttgagcct 420
gaaattcgga tagtgaacgg gaagccaaag aaagtccgga aaccccgcac catctactcc 480
agtttccagc tggcggctct tcagcggcgt ttccaaaaga ctcaatactt ggccttgccg 540
gagcgagccg agctggcggc ctctctgggc ctcacccaga ctcaggtcaa aatctggttc 600
cagaaccgcc ggtccaagtt caagaagatg tggaaaagtg gtgagatccc ctcggagcag 660
caccctgggg ccagcgcttc tccaccttgt gcttcgccgc cagtctcagc gccggcctcc 720
tgggactttg gtgtgccgca gcggatggcg ggcggcggtg gtccgggcag tggcggcagc 780
ggcgccggca gctcgggctc cagcccgagc agcgcggcct cggcttttct gggcaactac 840
ccctggtacc accagacctc gggatccgcc tcacacctgc aggccacggc gccgctgctg 900
caccccactc agaccccgca gccgcatcac caccaccacc atcacggcgg cgggggcgcc 960
ccggtgagcg cggggacgat tttctaa 987
<210> 101
<211> 1566
<212> DNA
<213> 人类
<400> 101
atggcatcaa acagcctctt cagcacagtg acaccatgtc agcaaaactt cttttgggat 60
ccgagcacca gccggcgctt cagccccccc tccagcagcc tgcagcccgg caaaatgagc 120
gacgtgagcc cggtggtggc tgcgcaacag cagcagcaac agcagcagca gcaacagcag 180
cagcagcagc agcaacagca gcagcagcag caggaggcgg cggcggcggc tgcggcggcg 240
gcggcggctg cggcggcggc agctgcagtg ccccggttgc ggccgcccca cgacaaccgc 300
accatggtgg agatcatcgc cgaccacccg gccgaactcg tccgcaccga cagccccaac 360
ttcctgtgct cggtgctgcc ctcgcactgg cgctgcaaca agaccctgcc cgtggccttc 420
aaggtggtag ccctcggaga ggtaccagat gggactgtgg ttactgtcat ggcgggtaac 480
gatgaaaatt attctgctga gctccggaat gcctctgctg ttatgaaaaa ccaagtagca 540
aggttcaacg atctgagatt tgtgggccgg agtggacgag gcaagagttt caccttgacc 600
ataaccgtct tcacaaatcc tccccaagta gctacctatc acagagcaat taaagttaca 660
gtagatggac ctcgggaacc cagaaggcac agacagaagc ttgatgactc taaacctagt 720
ttgttctctg accgcctcag tgatttaggg cgcattcctc atcccagtat gagagtaggt 780
gtcccgcctc agaacccacg gccctccctg aactctgcac caagtccttt taatccacaa 840
ggacagagtc agattacaga ccccaggcag gcacagtctt ccccgccgtg gtcctatgac 900
cagtcttacc cctcctacct gagccagatg acgtccccgt ccatccactc taccaccccg 960
ctgtcttcca cacggggcac tgggcttcct gccatcaccg atgtgcctag gcgcatttca 1020
gatgatgaca ctgccacctc tgacttctgc ctctggcctt ccactctcag taagaagagc 1080
caggcaggtg cttcagaact gggccctttt tcagacccca ggcagttccc aagcatttca 1140
tccctcactg agagccgctt ctccaaccca cgaatgcact atccagccac ctttacttac 1200
accccgccag tcacctcagg catgtccctc ggtatgtccg ccaccactca ctaccacacc 1260
tacctgccac caccctaccc cggctcttcc caaagccaga gtggaccctt ccagaccagc 1320
agcactccat atctctacta tggcacttcg tcaggatcct atcagtttcc catggtgccg 1380
gggggagacc ggtctccttc cagaatgctt ccgccatgca ccaccacctc gaatggcagc 1440
acgctattaa atccaaattt gcctaaccag aatgatggtg ttgacgctga tggaagccac 1500
agcagttccc caactgtttt gaattctagt ggcagaatgg atgaatctgt ttggcgacca 1560
tattga 1566
<210> 102
<211> 2292
<212> DNA
<213> 人类
<400> 102
atgcttactg accctgattt acctcaggag tttgaaagga tgtcttccaa gcgaccagcc 60
tctccgtatg gggaagcaga tggagaggta gccatggtga caagcagaca gaaagtggaa 120
gaagaggaga gtgacgggct cccagccttt caccttccct tgcatgtgag ttttcccaac 180
aagcctcact ctgaggaatt tcagccagtt tctctgctga cgcaagagac ttgtggccat 240
aggactccca cttctcagca caatacaatg gaagttgatg gcaataaagt tatgtcttca 300
tttgccccac acaactcatc tacctcacct cagaaggcag aagaaggtgg gcgacagagt 360
ggcgagtcct tgtctagtac agccctggga actcctgaac ggcgcaaggg cagtttagct 420
gatgttgttg acaccttgaa gcagaggaaa atggaagagc tcatcaaaaa cgagccggaa 480
gaaaccccca gtattgaaaa actactctca aaggactgga aagacaagct tcttgcaatg 540
ggatcgggga actttggcga aataaaaggg actcccgaga gcttagctga gaaagaaagg 600
caactcatgg gtatgatcaa ccagctgacc agcctccgag agcagctgtt ggctgcccac 660
gatgagcaga agaaactagc tgcctctcag attgagaaac agcgtcagca aatggagctg 720
gccaagcagc aacaagaaca aattgcaaga cagcagcagc agcttctaca gcaacaacac 780
aaaatcaatt tgctccagca acagatccag gttcaaggtc agctgccgcc attaatgatt 840
cccgtattcc ctcctgatca acggacactg gctgcagctg cccagcaagg attcctcctc 900
cctccaggct tcagctataa ggctggatgt agtgaccctt accctgttca gctgatccca 960
actaccatgg cagctgctgc cgcagcaaca ccaggcttag gcccactcca actgcagcag 1020
ttatatgctg cccagctagc tgcaatgcag gtatctccag gagggaagct gccaggcata 1080
ccccaaggca accttggtgc tgctgtatct cctaccagca ttcacacaga caagagcaca 1140
aacagcccac cacccaaaag caaggatgaa gtggcacagc cactgaacct atcagctaaa 1200
cccaagacct ctgatggcaa atcacccaca tcacccacct ctccccatat gccagctctg 1260
agaataaaca gtggggcagg ccccctcaaa gcctctgtcc cagcagcgtt agctagtcct 1320
tcagccagag ttagcacaat aggttactta aatgaccatg atgctgtcac caaggcaatc 1380
caagaagctc ggcaaatgaa ggagcaactc cgacgggaac aacaggtgct tgatgggaag 1440
gtggctgttg tgaatagtct gggtctcaat aactgccgaa cagaaaagga aaaaacaaca 1500
ctggagagtc tgactcagca actggcagtt aaacagaatg aagaaggaaa atttagccat 1560
gcaatgatgg atttcaatct gagtggagat tctgatggaa gtgctggagt ctcagagtca 1620
agaatttata gggaatcccg agggcgtggt agcaatgaac cccacataaa gcgtccaatg 1680
aatgccttca tggtgtgggc taaagatgaa cggagaaaga tccttcaagc ctttcctgac 1740
atgcacaact ccaacatcag caagatattg ggatctcgct ggaaagctat gacaaaccta 1800
gagaaacagc catattatga ggagcaagcc cgtctcagca agcagcacct ggagaagtac 1860
cctgactata agtacaagcc caggccaaag cgcacctgcc tggtggatgg caaaaagctg 1920
cgcattggtg aatacaaggc aatcatgcgc aacaggcggc aggaaatgcg gcagtacttc 1980
aatgttgggc aacaagcaca gatccccatt gccactgctg gtgttgtgta ccctggagcc 2040
atcgccatgg ctgggatgcc ctcccctcac ctgccctcgg agcactcaag cgtgtctagc 2100
agcccagagc ctgggatgcc tgttatccag agcacttacg gtgtgaaagg agaggagcca 2160
catatcaaag aagagataca ggccgaggac atcaatggag aaatttatga tgagtacgac 2220
gaggaagagg atgatccaga tgtagattat gggagtgaca gtgaaaacca tattgcagga 2280
caagccaact ga 2292
<210> 103
<211> 2427
<212> DNA
<213> 人类
<400> 103
atgtcttcca agcaagccac ctctccattt gcctgtgcag ctgatggaga ggatgcaatg 60
acccaggatt taacctcaag ggaaaaggaa gagggcagtg atcaacatgt ggcctcccat 120
ctgcctctgc accccataat gcacaacaaa cctcactctg aggagctacc aacacttgtc 180
agtaccattc aacaagatgc tgactgggac agcgttctgt catctcagca aagaatggaa 240
tcagagaata ataagttatg ttccctatat tccttccgaa atacctctac ctcaccacat 300
aagcctgacg aagggagtcg ggaccgtgag ataatgacca gtgttacttt tggaacccca 360
gagcgccgca aagggagtct tgccgatgtg gtggacacac tgaaacagaa gaagcttgag 420
gaaatgactc ggactgaaca agaggattcc tcctgcatgg aaaaactact ttcaaaagat 480
tggaaggaaa aaatggaaag actaaatacc agtgaacttc ttggagaaat taaaggtaca 540
cctgagagcc tggcagaaaa agaacggcag ctctccacca tgattaccca gctgatcagt 600
ttacgggagc agctactggc agcgcatgat gaacagaaaa aactggcagc gtcacaaatt 660
gagaaacaac ggcagcaaat ggaccttgct cgccaacagc aagaacagat tgcgagacaa 720
cagcagcaac ttctgcaaca gcagcacaaa attaatctcc tgcagcaaca gatccaggtt 780
cagggtcaca tgcctccgct catgatccca atttttccac atgaccagcg gactctggca 840
gcagctgctg ctgcccaaca gggattcctc ttcccccctg gaataacata caaaccaggt 900
gataactacc ccgtacagtt cattccatca acaatggcag ctgctgctgc ttctggactc 960
agccctttac agctccagaa gggtcatgcc tcccacccac aaattaacca aaggctaaag 1020
ggcctaagtg accgttttgg caggaatttg gacacctttg aacatggtgg tggccactct 1080
tacaaccaca aacagattga gcagctctat gccgctcagc tggccagcat gcaggtgtca 1140
cctggagcaa agatgccatc aactccacag ccaccaaaca cagcagggac ggtctcacct 1200
actgggataa aaaatgaaaa gagagggacc agccctgtaa ctcaagttaa ggatgaagca 1260
gcagcacagc ctctgaatct ctcatcccga cccaagacag cagagcctgt aaagtcccca 1320
acgtctccca cccagaacct cttcccagcc agcaaaacca gccctgtcaa tctgccaaac 1380
aaaagcagca tccctagccc cattggagga agcctgggaa gaggatcctc tttagatatc 1440
ctatctagtc tcaactcccc tgcccttttt ggggatcagg atacagtgat gaaagccatt 1500
caggaggcgc ggaagatgcg agagcagatc cagcgggagc aacagcagca acagccacat 1560
ggtgttgacg ggaaactgtc ctccataaat aatatggggc tgaacagctg caggaatgaa 1620
aaggaaagaa cgcgctttga gaatttgggg ccccagttaa cgggaaagtc aaatgaagat 1680
ggaaaactgg gcccaggtgt catcgacctt actcggccag aagatgcaga gggaggtgcc 1740
actgtggctg aagcacgagt ctacagggac gcccgcggcc gtgccagcag cgagccacac 1800
attaagcgac caatgaatgc attcatggtt tgggcaaagg atgagaggag aaaaatcctt 1860
caggccttcc ccgacatgca taactccaac attagcaaaa tcttaggatc tcgctggaaa 1920
tcaatgtcca accaggagaa gcaaccttat tatgaagagc aggcccggct aagcaagatc 1980
cacttagaga agtacccaaa ctataaatac aaaccccgac cgaaacgcac ctgcattgtt 2040
gatggcaaaa agcttcggat tggggagtat aagcaactga tgaggtctcg gagacaggag 2100
atgaggcagt tctttactgt ggggcaacag cctcagattc caatcaccac aggaacaggt 2160
gttgtgtatc ctggtgctat cactatggca actaccacac catcgcctca gatgacatct 2220
gactgctcta gcacctcggc cagcccggag cccagcctcc cggtcatcca gagcacttat 2280
ggtatgaaga cagatggcgg aagcctagct ggaaatgaaa tgatcaatgg agaggatgaa 2340
atggaaatgt atgatgacta tgaagatgac cccaaatcag actatagcag tgaaaatgaa 2400
gccccggagg ctgtcagtgc caactga 2427
<210> 104
<211> 1788
<212> DNA
<213> 人类
<400> 104
atggccttga ctgacggcgg ctggtgcttg ccgaagcgct tcggggccgc gggtgcggac 60
gccagcgact ccagagcctt tccagcgcgg gagccctcca cgccgccttc ccccatctct 120
tcctcgtcct cctcctgctc ccggggcgga gagcggggcc ccggcggcgc cagcaactgc 180
gggacgcctc agctcgacac ggaggcggcg gccggacccc cggcccgctc gctgctgctc 240
agttcctacg cttcgcatcc cttcggggct ccccacggac cttcggcgcc tggggtcgcg 300
ggccccgggg gcaacctgtc gagctgggag gacttgctgc tgttcactga cctcgaccaa 360
gccgcgaccg ccagcaagct gctgtggtcc agccgcggcg ccaagctgag ccccttcgca 420
cccgagcagc cggaggagat gtaccagacc ctcgccgctc tctccagcca gggtccggcc 480
gcctacgacg gcgcgcccgg cggcttcgtg cactctgcgg ccgcggcggc agcagccgcg 540
gcggcggcca gctccccggt ctacgtgccc accacccgcg tgggttccat gctgcccggc 600
ctaccgtacc acctgcaggg gtcgggcagt gggccagcca accacgcggg cggcgcgggc 660
gcgcaccccg gctggcctca ggcctcggcc gacagccctc catacggcag cggaggcggc 720
gcggctggcg gcggggccgc ggggcctggc ggcgctggct cagccgcggc gcacgtctcg 780
gcgcgcttcc cctactctcc cagcccgccc atggccaacg gcgccgcgcg ggagccggga 840
ggctacgcgg cggcgggcag tgggggcgcg ggaggcgtga gcggcggcgg cagtagcctg 900
gcggccatgg gcggccgcga gccccagtac agctcgctgt cggccgcgcg gccgctgaac 960
gggacgtacc accaccacca ccaccaccac caccaccatc cgagccccta ctcgccctac 1020
gtgggggcgc cactgacgcc tgcctggccc gccggaccct tcgagacccc ggtgctgcac 1080
agcctgcaga gccgcgccgg agccccgctc ccggtgcccc ggggtcccag tgcagacctg 1140
ctggaggacc tgtccgagag ccgcgagtgc gtgaactgcg gctccatcca gacgccgctg 1200
tggcggcggg acggcaccgg ccactacctg tgcaacgcct gcgggctcta cagcaagatg 1260
aacggcctca gccggcccct catcaagccg cagaagcgcg tgccttcatc acggcggctt 1320
ggattgtcct gtgccaactg tcacaccaca actaccacct tatggcgcag aaacgccgag 1380
ggtgaacccg tgtgcaatgc ttgtggactc tacatgaaac tccatggggt gcccagacca 1440
cttgctatga aaaaagaggg aattcaaacc aggaaacgaa aacctaagaa cataaataaa 1500
tcaaagactt gctctggtaa tagcaataat tccattccca tgactccaac ttccacctct 1560
tctaactcag atgattgcag caaaaatact tcccccacaa cacaacctac agcctcaggg 1620
gcgggtgccc cggtgatgac tggtgcggga gagagcacca atcccgagaa cagcgagctc 1680
aagtattcgg gtcaagatgg gctctacata ggcgtcagtc tcgcctcgcc ggccgaagtc 1740
acgtcctccg tgcgaccgga ttcctggtgc gccctggccc tggcctga 1788
<210> 105
<211> 1242
<212> DNA
<213> 人类
<400> 105
atggagttcc ctggcctggg gtccctgggg acctcagagc ccctccccca gtttgtggat 60
cctgctctgg tgtcctccac accagaatca ggggttttct tcccctctgg gcctgagggc 120
ttggatgcag cagcttcctc cactgccccg agcacagcca ccgctgcagc tgcggcactg 180
gcctactaca gggacgctga ggcctacaga cactccccag tctttcaggt gtacccattg 240
ctcaactgta tggaggggat cccagggggc tcaccatatg ccggctgggc ctacggcaag 300
acggggctct accctgcctc aactgtgtgt cccacccgcg aggactctcc tccccaggcc 360
gtggaagatc tggatggaaa aggcagcacc agcttcctgg agactttgaa gacagagcgg 420
ctgagcccag acctcctgac cctgggacct gcactgcctt catcactccc tgtccccaat 480
agtgcttatg ggggccctga cttttccagt accttctttt ctcccaccgg gagccccctc 540
aattcagcag cctattcctc tcccaagctt cgtggaactc tccccctgcc tccctgtgag 600
gccagggagt gtgtgaactg cggagcaaca gccactccac tgtggcggag ggacaggaca 660
ggccactacc tatgcaacgc ctgcggcctc tatcacaaga tgaatgggca gaacaggccc 720
ctcatccggc ccaagaagcg cctgattgtc agtaaacggg caggtactca gtgcaccaac 780
tgccagacga ccaccacgac actgtggcgg agaaatgcca gtggggatcc cgtgtgcaat 840
gcctgcggcc tctactacaa gctacaccag gtgaaccggc cactgaccat gcggaaggat 900
ggtattcaga ctcgaaaccg caaggcatct ggaaaaggga aaaagaaacg gggctccagt 960
ctgggaggca caggagcagc cgaaggacca gctggtggct ttatggtggt ggctgggggc 1020
agcggtagcg ggaattgtgg ggaggtggct tcaggcctga cactgggccc cccaggtact 1080
gcccatctct accaaggcct gggccctgtg gtgctgtcag ggcctgttag ccacctcatg 1140
cctttccctg gacccctact gggctcaccc acgggctcct tccccacagg ccccatgccc 1200
cccaccacca gcactactgt ggtggctccg ctcagctcat ga 1242
<210> 106
<211> 1359
<212> DNA
<213> 人类
<400> 106
atggacggga ctattaagga ggctctgtcg gtggtgagcg acgaccagtc cctctttgac 60
tcagcgtacg gagcggcagc ccatctcccc aaggccgaca tgactgcctc ggggagtcct 120
gactacgggc agccccacaa gatcaacccc ctcccaccac agcaggagtg gatcaatcag 180
ccagtgaggg tcaacgtcaa gcgggagtat gaccacatga atggatccag ggagtctccg 240
gtggactgca gcgttagcaa atgcagcaag ctggtgggcg gaggcgagtc caaccccatg 300
aactacaaca gctatatgga cgagaagaat ggcccccctc ctcccaacat gaccaccaac 360
gagaggagag tcatcgtccc cgcagacccc acactgtgga cacaggagca tgtgaggcaa 420
tggctggagt gggccataaa ggagtacagc ttgatggaga tcgacacatc ctttttccag 480
aacatggatg gcaaggaact gtgtaaaatg aacaaggagg acttcctccg cgccaccacc 540
ctctacaaca cggaagtgct gttgtcacac ctcagttacc tcagggaaag ttcactgctg 600
gcctataata caacctccca caccgaccaa tcctcacgat tgagtgtcaa agaagaccct 660
tcttatgact cagtcagaag aggagcttgg ggcaataaca tgaattctgg cctcaacaaa 720
agtcctcccc ttggaggggc acaaacgatc agtaagaata cagagcaacg gccccagcca 780
gatccgtatc agatcctggg cccgaccagc agtcgcctag ccaaccctgg aagcgggcag 840
atccagctgt ggcaattcct cctggagctg ctctccgaca gcgccaacgc cagctgtatc 900
acctgggagg ggaccaacgg ggagttcaaa atgacggacc ccgatgaggt ggccaggcgc 960
tggggcgagc ggaaaagcaa gcccaacatg aattacgaca agctgagccg ggccctccgt 1020
tattactatg ataaaaacat tatgaccaaa gtgcacggca aaagatatgc ttacaaattt 1080
gacttccacg gcattgccca ggctctgcag ccacatccga ccgagtcgtc catgtacaag 1140
tacccttctg acatctccta catgccttcc taccatgccc accagcagaa ggtgaacttt 1200
gtccctcccc atccatcctc catgcctgtc acttcctcca gcttctttgg agccgcatca 1260
caatactgga cctcccccac ggggggaatc taccccaacc ccaacgtccc ccgccatcct 1320
aacacccacg tgccttcaca cttaggcagc tactactag 1359
<210> 107
<211> 1089
<212> DNA
<213> 人类
<400> 107
atggccacag ccgagaccgc cttgccctcc atcagcacac tgaccgccct gggccccttc 60
ccggacacac aggatgactt cctcaagtgg tggcgctccg aagaggcgca ggacatgggc 120
ccgggtcctc ctgaccccac ggagccgccc ctccacgtga agtctgagga ccagcccggg 180
gaggaagagg acgatgagag gggcgcggac gccacctggg acctggatct cctcctcacc 240
aacttctcgg gcccggagcc cggtggcgcg ccccagacct gcgctctggc gcccagcgag 300
gcctccgggg cgcaatatcc gccgccgccc gagactctgg gcgcatatgc tggcggcccg 360
gggctggtgg ctgggctttt gggttcggag gatcactcgg gttgggtgcg ccctgccctg 420
cgagcccggg ctcccgacgc cttcgtgggc ccagccctgg ctccagcccc ggcccccgag 480
cccaaggcgc tggcgctgca accggtgtac ccggggcccg gcgccggctc ctcgggtggc 540
tacttcccgc ggaccgggct ttcagtgcct gcggcgtcgg gcgcccccta cgggctactg 600
tccgggtacc ccgcgatgta cccggcgcct cagtaccaag ggcacttcca gctcttccgc 660
gggctccagg gacccgcgcc cggtcccgcc acgtccccct ccttcctgag ttgtttggga 720
cccgggacgg tgggcactgg actcgggggg actgcagagg atccaggtgt gatagccgag 780
accgcgccat ccaagcgagg ccgacgttcg tgggcgcgca agaggcaggc agcgcacacg 840
tgcgcgcacc cgggttgcgg caagagctac accaagagct cccacctgaa ggcgcatctg 900
cgcacgcaca caggggagaa gccatacgcc tgcacgtggg aaggctgcgg ctggagattc 960
gcgcgctcgg acgagctgac ccgccactac cggaaacaca cggggcagcg ccccttccgc 1020
tgccagctct gcccacgtgc tttttcgcgc tctgaccacc tggccttgca catgaagcgc 1080
cacctttga 1089
<210> 108
<211> 960
<212> DNA
<213> 人类
<400> 108
atggagctac tgtcgccacc gctccgcgac gtagacctga cggcccccga cggctctctc 60
tgctcctttg ccacaacgga cgacttctat gacgacccgt gtttcgactc cccggacctg 120
cgcttcttcg aagacctgga cccgcgcctg atgcacgtgg gcgcgctcct gaaacccgaa 180
gagcactcgc acttccccgc ggcggtgcac ccggccccgg gcgcacgtga ggacgagcat 240
gtgcgcgcgc ccagcgggca ccaccaggcg ggccgctgcc tactgtgggc ctgcaaggcg 300
tgcaagcgca agaccaccaa cgccgaccgc cgcaaggccg ccaccatgcg cgagcggcgc 360
cgcctgagca aagtaaatga ggcctttgag acactcaagc gctgcacgtc gagcaatcca 420
aaccagcggt tgcccaaggt ggagatcctg cgcaacgcca tccgctatat cgagggcctg 480
caggctctgc tgcgcgacca ggacgccgcg ccccctggcg cagccgcctt ctatgcgccg 540
ggcccgctgc ccccgggccg cggcggcgag cactacagcg gcgactccga cgcgtccagc 600
ccgcgctcca actgctccga cggcatgatg gactacagcg gccccccgag cggcgcccgg 660
cggcggaact gctacgaagg cgcctactac aacgaggcgc ccagcgaacc caggcccggg 720
aagagtgcgg cggtgtcgag cctagactac ctgtccagca tcgtggagcg catctccacc 780
gagagccctg cggcgcccgc cctcctgctg gcggacgtgc cttctgagtc gcctccgcgc 840
aggcaagagg ctgccgcccc cagcgaggga gagagcagcg gcgaccccac ccagtcaccg 900
gacgccgccc cgcagtgccc tgcgggtgcg aaccccaacc cgatatacca ggtgctctga 960
<210> 109
<211> 1578
<212> DNA
<213> 人类
<400> 109
atgcacagag cgccttcccc cacagccgag cagccgccgg gcggagggga cagcgcccgc 60
cggaccctgc agcccagact caagcccagt gcccgagcca tggcactgcc tcggacgctg 120
ggggagctgc agctgtaccg ggtcctgcag cgcgccaacc tcctttccta ctatgagacc 180
ttcatccagc agggagggga cgacgtgcag cagctgtgtg aggcgggtga ggaggagttt 240
ctggagatca tggcacttgt gggcatggcc accaagcccc tccatgtccg gcgcctgcag 300
aaggcactga gagagtgggc caccaatcca gggctcttca gtcaaccagt gcctgctgtt 360
cccgtctcca gcatcccgct cttcaagatc tctgagactg cgggtacccg gaaagggagc 420
atgagcaatg ggcatggcag cccaggggaa aaggcaggca gtgcccgcag ttttagcccc 480
aagagccccc ttgaacttgg agagaagcta tcaccactgc ctgggggacc tggggcaggg 540
gacccccgga tctggccagg ccggagcact ccagagtcgg acgttggggc aggaggagaa 600
gaggaggctg gctcgccccc cttctccccc cctgcagggg gaggagtccc tgaggggact 660
ggggctgggg ggctggcagc aggtgggact gggggtggtc cagaccgact ggagccagag 720
atggtacgca tggtggtgga aagtgtggag aggatcttcc ggagcttccc aaggggggat 780
gctggggagg tcacatccct gctaaagctg aataagaagc tggcacggag cgttgggcac 840
atctttgaga tggatgataa tgacagccag aaggaagagg agatccgcaa atacagcatc 900
atctatggcc gtttcgactc taagcggcgg gagggcaagc agctcagcct gcacgagctc 960
accatcaacg aggctgctgc ccagttctgc atgagggaca acacgctctt attacggaga 1020
gtggagctct tctctttgtc ccgccaagta gcccgagaga gcacctactt gtcctccttg 1080
aagggctcca ggcttcaccc tgaagaactg ggaggccctc cactgaagaa gctgaaacaa 1140
gaggttggag aacagagtca ccctgaaatc cagcagcctc ccccaggccc tgagtcctat 1200
gtacccccat accgccccag cctggaggag gacagcgcca gcctgtctgg ggagagtctg 1260
gatggacatt tgcaggctgt ggggtcatgt ccaaggctga cgccgccccc tgctgacctg 1320
cctctggcat tgccagccca tgggctatgg agccgacaca tcctgcagca gacactgatg 1380
gacgaggggc tgcggctcgc ccgcctcgtc tcccacgacc gcgtgggccg cctcagcccc 1440
tgtgtgcctg cgaagccacc tctcgcagag ttcgaggaag ggctgctgga cagatgtcct 1500
gccccaggac cccatcccgc gctggtggag ggtcgcagga gcagcgtgaa agtggaggct 1560
gaggccagcc ggcagtga 1578
<210> 110
<211> 1632
<212> DNA
<213> 人类
<400> 110
atggccgcgg ccaaggccga gatgcagctg atgtccccgc tgcagatctc tgacccgttc 60
ggatcctttc ctcactcgcc caccatggac aactacccta agctggagga gatgatgctg 120
ctgagcaacg gggctcccca gttcctcggc gccgccgggg ccccagaggg cagcggcagc 180
aacagcagca gcagcagcag cgggggcggt ggaggcggcg ggggcggcag caacagcagc 240
agcagcagca gcaccttcaa ccctcaggcg gacacgggcg agcagcccta cgagcacctg 300
accgcagagt cttttcctga catctctctg aacaacgaga aggtgctggt ggagaccagt 360
taccccagcc aaaccactcg actgcccccc atcacctata ctggccgctt ttccctggag 420
cctgcaccca acagtggcaa caccttgtgg cccgagcccc tcttcagctt ggtcagtggc 480
ctagtgagca tgaccaaccc accggcctcc tcgtcctcag caccatctcc agcggcctcc 540
tccgcctccg cctcccagag cccacccctg agctgcgcag tgccatccaa cgacagcagt 600
cccatttact cagcggcacc caccttcccc acgccgaaca ctgacatttt ccctgagcca 660
caaagccagg ccttcccggg ctcggcaggg acagcgctcc agtacccgcc tcctgcctac 720
cctgccgcca agggtggctt ccaggttccc atgatccccg actacctgtt tccacagcag 780
cagggggatc tgggcctggg caccccagac cagaagccct tccagggcct ggagagccgc 840
acccagcagc cttcgctaac ccctctgtct actattaagg cctttgccac tcagtcgggc 900
tcccaggacc tgaaggccct caataccagc taccagtccc agctcatcaa acccagccgc 960
atgcgcaagt accccaaccg gcccagcaag acgccccccc acgaacgccc ttacgcttgc 1020
ccagtggagt cctgtgatcg ccgcttctcc cgctccgacg agctcacccg ccacatccgc 1080
atccacacag gccagaagcc cttccagtgc cgcatctgca tgcgcaactt cagccgcagc 1140
gaccacctca ccacccacat ccgcacccac acaggcgaaa agcccttcgc ctgcgacatc 1200
tgtggaagaa agtttgccag gagcgatgaa cgcaagaggc ataccaagat ccacttgcgg 1260
cagaaggaca agaaagcaga caaaagtgtt gtggcctctt cggccacctc ctctctctct 1320
tcctacccgt ccccggttgc tacctcttac ccgtccccgg ttactacctc ttatccatcc 1380
ccggccacca cctcataccc atcccctgtg cccacctcct tctcctctcc cggctcctcg 1440
acctacccat cccctgtgca cagtggcttc ccctccccgt cggtggccac cacgtactcc 1500
tctgttcccc ctgctttccc ggcccaggtc agcagcttcc cttcctcagc tgtcaccaac 1560
tccttcagcg cctccacagg gctttcggac atgacagcaa ccttttctcc caggacaatt 1620
gaaatttgct aa 1632
<210> 111
<211> 1269
<212> DNA
<213> 人类
<400> 111
atgccgcgct catttctcgt caaaagcaag aaggctcaca gctaccacca gccgcgctcc 60
ccaggaccag actattccct ccgtttagag aatgtaccgg cgcctagccg agcagacagc 120
acttcaaatg caggcggggc gaaggcggag ccccgggacc gtttgtcccc cgaatcgcag 180
ctgaccgaag ccccagacag agcctccgca tccccagaca gctgcgaagg cagcgtctgc 240
gaacggagct cggagtttga ggacttctgg aggcccccgt caccctccgc gtctccagcc 300
tcggagaagt caatgtgccc atcgctggac gaagcccagc ccttccccct gcctttcaaa 360
ccgtactcat ggagcggcct ggcgggttct gacctgcggc acctggtgca gagctaccga 420
ccgtgtgggg ccctggagcg tggcgctggc ctgggcctct tctgcgaacc cgccccggag 480
cctggccacc cggccgcgct gtacggcccg aagcgggctg ccggcggcgc gggggccggg 540
gcgccaggga gctgcagcgc aggggccggt gccaccgctg gccctggcct agggctctac 600
ggcgacttcg ggtctgcggc agccgggctg tatgagaggc ccacggcagc ggcgggcttg 660
ctgtaccccg agcgtggcca cgggctgcac gcagacaagg gcgctggcgt caaggtggag 720
tcggagctgc tgtgcacccg cctgctgctg ggcggcggct cctacaagtg catcaagtgc 780
agcaaggtgt tctccacgcc gcacgggctc gaggtgcacg tgcgcaggtc ccacagcggt 840
accagaccct ttgcctgcga gatgtgcggc aagaccttcg ggcacgcggt gagcctggag 900
cagcacaaag ccgtgcactc gcaggaacgg agctttgact gtaagatctg tgggaagagc 960
ttcaagaggt catccacact gtccacacac ctgcttatcc actcagacac tcggccctac 1020
ccctgtcagt actgtggcaa gaggttccac cagaagtcag acatgaagaa acacactttc 1080
atccacactg gtgagaagcc tcacaagtgc caggtgtgcg gcaaggcatt cagccagagc 1140
tccaacctca tcacccacag ccgcaaacac acaggcttca agcccttcgg ctgcgacctc 1200
tgtgggaagg gtttccagag gaaggtggac ctccgaaggc accgggagac gcagcatggg 1260
ctcaaatga 1269
<210> 112
<211> 1176
<212> DNA
<213> 人类
<400> 112
atggatttag agaaaaatta tccgactcct cggaccagca ggacaggaca tggaggagtg 60
aatcagcttg ggggggtttt tgtgaatgga cggccactcc cggatgtagt ccgccagagg 120
atagtggaac ttgctcatca aggtgtcagg ccctgcgaca tctccaggca gcttcgggtc 180
agccatggtt gtgtcagcaa aattcttggc aggtattatg agacaggaag catcaagcct 240
ggggtaattg gaggatccaa accaaaggtc gccacaccca aagtggtgga aaaaatcgct 300
gaatataaac gccaaaatcc caccatgttt gcctgggaga tcagggaccg gctgctggca 360
gagcgggtgt gtgacaatga caccgtgcct agcgtcagtt ccatcaacag gatcatccgg 420
acaaaagtac agcagccacc caaccaacca gtcccagctt ccagtcacag catagtgtcc 480
actggctccg tgacgcaggt gtcctcggtg agcacggatt cggccggctc gtcgtactcc 540
atcagcggca tcctgggcat cacgtccccc agcgccgaca ccaacaagcg caagagagac 600
gaaggtattc aggagtctcc ggtgccgaac ggccactcgc ttccgggcag agacttcctc 660
cggaagcaga tgcggggaga cttgttcaca cagcagcagc tggaggtgct ggaccgcgtg 720
tttgagaggc agcactactc agacatcttc accaccacag agcccatcaa gcccgagcag 780
accacagagt attcagccat ggcctcgctg gctggtgggc tggacgacat gaaggccaat 840
ctggccagcc ccacccctgc tgacatcggg agcagtgtgc caggcccgca gtcctacccc 900
attgtgacag gccgtgactt ggcgagcacg accctccccg ggtaccctcc acacgtcccc 960
cccgctggac agggcagcta ctcagcaccg acgctgacag ggatggtgcc tgggagtgag 1020
ttttccggga gtccctacag ccaccctcag tattcctcgt acaacgactc ctggaggttc 1080
cccaacccgg ggctgcttgg ctccccctac tattatagcg ctgccgcccg aggagccgcc 1140
ccacctgcag ccgccactgc ctatgaccgt cactga 1176
<210> 113
<211> 1608
<212> DNA
<213> 人类
<400> 113
atgggcatcg tggagccggg ttgcggagac atgctgacgg gcaccgagcc gatgccgggg 60
agcgacgagg gccgggcgcc tggcgccgac ccgcagcacc gctacttcta cccggagccg 120
ggcgcgcagg acgcggacga gcgtcgcggg ggcggcagcc tggggtctcc ctacccgggg 180
ggcgccttgg tgcccgcccc gccgagccgc ttccttggag cctacgccta cccgccgcga 240
ccccaggcgg ccggcttccc cggcgcgggc gagtccttcc cgccgcccgc ggacgccgag 300
ggctaccagc cgggcgaggg ctacgccgcc ccggacccgc gcgccgggct ctacccgggg 360
ccgcgtgagg actacgcgct acccgcggga ctggaggtgt cggggaaact gagggtcgcg 420
ctcaacaacc acctgttgtg gtccaagttt aatcagcacc agacagagat gatcatcacc 480
aagcagggac ggcggatgtt cccattcctg tcatttactg tggccgggct ggagcccacc 540
agccactaca ggatgtttgt ggacgtggtc ttggtggacc agcaccactg gcggtaccag 600
agcggcaagt gggtgcagtg tggaaaggcc gagggcagca tgccaggaaa ccgcctgtac 660
gtccacccgg actcccccaa cacaggagcg cactggatgc gccaggaagt ttcatttggg 720
aaactaaagc tcacaaacaa caagggggcg tccaacaatg tgacccagat gattgtgctc 780
cagtccctcc ataagtacca gccccggctg catatcgttg aggtgaacga cggagagcca 840
gaggcagcct gcaacgcttc caacacgcat atctttactt tccaagaaac ccagttcatt 900
gccgtgactg cctaccagaa tgccgagatt actcagctga aaattgataa taaccccttt 960
gccaaaggat tccgggagaa ctttgagtcc atgtacacat ctgttgacac cagcatcccc 1020
tccccgcctg gacccaactg tcaattcctt gggggagatc actactctcc tctcctaccc 1080
aaccagtatc ctgttcccag ccgcttctac cccgaccttc ctggccaggc gaaggatgtg 1140
gttccccagg cttactggct gggggccccc cgggaccaca gctatgaggc tgagtttcga 1200
gcagtcagca tgaagcctgc attcttgccc tctgcccctg ggcccaccat gtcctactac 1260
cgaggccagg aggtcctggc acctggagct ggctggcctg tggcacccca gtaccctccc 1320
aagatgggcc cggccagctg gttccgccct atgcggactc tgcccatgga acccggccct 1380
ggaggctcag agggacgggg accagaggac cagggtcccc ccttggtgtg gactgagatt 1440
gcccccatcc ggccggaatc cagtgattca ggactgggcg aaggagactc taagaggagg 1500
cgcgtgtccc cctatccttc cagtggtgac agctcctccc ctgctggggc cccttctcct 1560
tttgataagg aagctgaagg acagttttat aactattttc ccaactga 1608
<210> 114
<211> 1335
<212> DNA
<213> 人类
<400> 114
atggaggtga cggcggacca gccgcgctgg gtgagccacc accaccccgc cgtgctcaac 60
gggcagcacc cggacacgca ccacccgggc ctcagccact cctacatgga cgcggcgcag 120
tacccgctgc cggaggaggt ggatgtgctt tttaacatcg acggtcaagg caaccacgtc 180
ccgccctact acggaaactc ggtcagggcc acggtgcaga ggtaccctcc gacccaccac 240
gggagccagg tgtgccgccc gcctctgctt catggatccc taccctggct ggacggcggc 300
aaagccctgg gcagccacca caccgcctcc ccctggaatc tcagcccctt ctccaagacg 360
tccatccacc acggctcccc ggggcccctc tccgtctacc ccccggcctc gtcctcctcc 420
ttgtcggggg gccacgccag cccgcacctc ttcaccttcc cgcccacccc gccgaaggac 480
gtctccccgg acccatcgct gtccacccca ggctcggccg gctcggcccg gcaggacgag 540
aaagagtgcc tcaagtacca ggtgcccctg cccgacagca tgaagctgga gtcgtcccac 600
tcccgtggca gcatgaccgc cctgggtgga gcctcctcgt cgacccacca ccccatcacc 660
acctacccgc cctacgtgcc cgagtacagc tccggactct tcccccccag cagcctgctg 720
ggcggctccc ccaccggctt cggatgcaag tccaggccca aggcccggtc cagcacagaa 780
ggcagggagt gtgtgaactg tggggcaacc tcgaccccac tgtggcggcg agatggcacg 840
ggacactacc tgtgcaacgc ctgcgggctc tatcacaaaa tgaacggaca gaaccggccc 900
ctcattaagc ccaagcgaag gctgtctgca gccaggagag cagggacgtc ctgtgcgaac 960
tgtcagacca ccacaaccac actctggagg aggaatgcca atggggaccc tgtctgcaat 1020
gcctgtgggc tctactacaa gcttcacaat attaacagac ccctgactat gaagaaggaa 1080
ggcatccaga ccagaaaccg aaaaatgtct agcaaatcca aaaagtgcaa aaaagtgcat 1140
gactcactgg aggacttccc caagaacagc tcgtttaacc cggccgccct ctccagacac 1200
atgtcctccc tgagccacat ctcgcccttc agccactcca gccacatgct gaccacgccc 1260
acgccgatgc acccgccatc cagcctgtcc tttggaccac accacccctc cagcatggtc 1320
accgccatgg gttag 1335
<210> 115
<211> 1296
<212> DNA
<213> 人类
<400> 115
atgcccaacc ccaggcctgg caagccctcg gccccttcct tggcccttgg cccatcccca 60
ggagcctcgc ccagctggag ggctgcaccc aaagcctcag acctgctggg ggcccggggc 120
ccagggggaa ccttccaggg ccgagatctt cgaggcgggg cccatgcctc ctcttcttcc 180
ttgaacccca tgccaccatc gcagctgcag ctgcccacac tgcccctagt catggtggca 240
ccctccgggg cacggctggg ccccttgccc cacttacagg cactcctcca ggacaggcca 300
catttcatgc accagctctc aacggtggat gcccacgccc ggacccctgt gctgcaggtg 360
caccccctgg agagcccagc catgatcagc ctcacaccac ccaccaccgc cactggggtc 420
ttctccctca aggcccggcc tggcctccca cctgggatca acgtggccag cctggaatgg 480
gtgtccaggg agccggcact gctctgcacc ttcccaaatc ccagtgcacc caggaaggac 540
agcacccttt cggctgtgcc ccagagctcc tacccactgc tggcaaatgg tgtctgcaag 600
tggcccggat gtgagaaggt cttcgaagag ccagaggact tcctcaagca ctgccaggcg 660
gaccatcttc tggatgagaa gggcagggca caatgtctcc tccagagaga gatggtacag 720
tctctggagc agcagctggt gctggagaag gagaagctga gtgccatgca ggcccacctg 780
gctgggaaaa tggcactgac caaggcttca tctgtggcat catccgacaa gggctcctgc 840
tgcatcgtag ctgctggcag ccaaggccct gtcgtcccag cctggtctgg cccccgggag 900
gcccctgaca gcctgtttgc tgtccggagg cacctgtggg gtagccatgg aaacagcaca 960
ttcccagagt tcctccacaa catggactac ttcaagttcc acaacatgcg accccctttc 1020
acctacgcca cgctcatccg ctgggccatc ctggaggctc cagagaagca gcggacactc 1080
aatgagatct accactggtt cacacgcatg tttgccttct tcagaaacca tcctgccacc 1140
tggaagaacg ccatccgcca caacctgagt ctgcacaagt gctttgtgcg ggtggagagc 1200
gagaaggggg ctgtgtggac cgtggatgag ctggagttcc gcaagaaacg gagccagagg 1260
cccagcaggt gttccaaccc tacacctggc ccctga 1296
<210> 116
<211> 1683
<212> DNA
<213> 人类
<400> 116
atggacaggg ccccacagag acagcaccga gcctcacggg agctgctggc tgcaaagaag 60
acccacacct cacaaattga agtgatccct tgcaaaatct gtggggacaa gtcgtctggg 120
atccactacg gggttatcac ctgtgagggg tgcaagggct tcttccgccg gagccagcgc 180
tgtaacgcgg cctactcctg cacccgtcag cagaactgcc ccatcgaccg caccagccga 240
aaccgatgcc agcactgccg cctgcagaaa tgcctggcgc tggggatgtc ccgagatgct 300
gtcaagttcg gccgcatgtc caagaagcag agggacagcc tgcatgcaga agtgcagaaa 360
cagctgcagc agcggcaaca gcagcaacag gaaccagtgg tcaagacccc tccagcaggg 420
gcccaaggag cagataccct cacctacacc ttggggctcc cagacgggca gctgcccctg 480
ggctcctcgc ctgacctgcc tgaggcttct gcctgtcccc ctggcctcct gaaagcctca 540
ggctctgggc cctcatattc caacaacttg gccaaggcag ggctcaatgg ggcctcatgc 600
caccttgaat acagccctga gcggggcaag gctgagggca gagagagctt ctatagcaca 660
ggcagccagc tgacccctga ccgatgtgga cttcgttttg aggaacacag gcatcctggg 720
cttggggaac tgggacaggg cccagacagc tacggcagcc ccagtttccg cagcacaccg 780
gaggcaccct atgcctccct gacagagata gagcacctgg tgcagagcgt ctgcaagtcc 840
tacagggaga catgccagct gcggctggag gacctgctgc ggcagcgctc caacatcttc 900
tcccgggagg aagtgactgg ctaccagagg aagtccatgt gggagatgtg ggaacggtgt 960
gcccaccacc tcaccgaggc cattcagtac gtggtggagt tcgccaagag gctctcaggc 1020
tttatggagc tctgccagaa tgaccagatt gtgcttctca aagcaggagc aatggaagtg 1080
gtgctggtta ggatgtgccg ggcctacaat gctgacaacc gcacggtctt ttttgaaggc 1140
aaatacggtg gcatggagct gttccgagcc ttgggctgca gcgagctcat cagctccatc 1200
tttgacttct cccactccct aagtgccttg cacttttccg aggatgagat tgccctctac 1260
acagcccttg ttctcatcaa tgcccatcgg ccagggctcc aagagaaaag gaaagtagaa 1320
cagctgcagt acaatctgga gctggccttt catcatcatc tctgcaagac tcatcgccaa 1380
agcatcctgg caaagctgcc acccaagggg aagcttcgga gcctgtgtag ccagcatgtg 1440
gaaaggctgc agatcttcca gcacctccac cccatcgtgg tccaagccgc tttccctcca 1500
ctctacaagg agctcttcag cactgaaacc gagtcacctg tgggctgtcc aagtgacctg 1560
gaagagggac tccttgcctc tccctatggc ctgctggcca cctccctgga ccccgttcca 1620
ccctcaccct tttcctttcc catgaaccct ggagggtggt ccccaccagc tctttggaag 1680
tga 1683
<210> 117
<211> 1395
<212> DNA
<213> 人类
<400> 117
atgcgactct ccaaaaccct cgtcgacatg gacatggccg actacagtgc tgcactggac 60
ccagcctaca ccaccctgga atttgagaat gtgcaggtgt tgacgatggg caatgacacg 120
tccccatcag aaggcaccaa cctcaacgcg cccaacagcc tgggtgtcag cgccctgtgt 180
gccatctgcg gggaccgggc cacgggcaaa cactacggtg cctcgagctg tgacggctgc 240
aagggcttct tccggaggag cgtgcggaag aaccacatgt actcctgcag atttagccgg 300
cagtgcgtgg tggacaaaga caagaggaac cagtgccgct actgcaggct caagaaatgc 360
ttccgggctg gcatgaagaa ggaagccgtc cagaatgagc gggaccggat cagcactcga 420
aggtcaagct atgaggacag cagcctgccc tccatcaatg cgctcctgca ggcggaggtc 480
ctgtcccgac agatcacctc ccccgtctcc gggatcaacg gcgacattcg ggcgaagaag 540
attgccagca tcgcagatgt gtgtgagtcc atgaaggagc agctgctggt tctcgttgag 600
tgggccaagt acatcccagc tttctgcgag ctccccctgg acgaccaggt ggccctgctc 660
agagcccatg ctggcgagca cctgctgctc ggagccacca agagatccat ggtgttcaag 720
gacgtgctgc tcctaggcaa tgactacatt gtccctcggc actgcccgga gctggcggag 780
atgagccggg tgtccatacg catccttgac gagctggtgc tgcccttcca ggagctgcag 840
atcgatgaca atgagtatgc ctacctcaaa gccatcatct tctttgaccc agatgccaag 900
gggctgagcg atccagggaa gatcaagcgg ctgcgttccc aggtgcaggt gagcttggag 960
gactacatca acgaccgcca gtatgactcg cgtggccgct ttggagagct gctgctgctg 1020
ctgcccacct tgcagagcat cacctggcag atgatcgagc agatccagtt catcaagctc 1080
ttcggcatgg ccaagattga caacctgttg caggagatgc tgctgggagg gtcccccagc 1140
gatgcacccc atgcccacca ccccctgcac cctcacctga tgcaggaaca tatgggaacc 1200
aacgtcatcg ttgccaacac aatgcccact cacctcagca acggacagat gtccacccct 1260
gagaccccac agccctcacc gccaggtggc tcagggtctg agccctataa gctcctgccg 1320
ggagccgtcg ccacaatcgt caagcccctc tctgccatcc cccagccgac catcaccaag 1380
caggaagtta tctag 1395
<210> 118
<211> 2385
<212> DNA
<213> 人类
<400> 118
atggcgggct ggatccaggc ccagcagctg cagggagacg cgctgcgcca gatgcaggtg 60
ctgtacggcc agcacttccc catcgaggtc cggcactact tggcccagtg gattgagagc 120
cagccatggg atgccattga cttggacaat ccccaggaca gagcccaagc cacccagctc 180
ctggagggcc tggtgcagga gctgcagaag aaggcggagc accaggtggg ggaagatggg 240
tttttactga agatcaagct gaggcactac gccacgcagc tccagaaaac atatgaccgc 300
tgccccctgg agctggtccg ctgcatccgg cacattctgt acaatgaaca gaggctggtc 360
cgagaagcca acaattgcag ctctccggct gggatcctgg ttgacgccat gtcccagaag 420
caccttcaga tcaaccagac atttgaggag ctgcgactgg tcacgcagga cacagagaat 480
gagctgaaga aactgcagca gactcaggag tacttcatca tccagtacca ggagagcctg 540
aggatccaag ctcagtttgc ccagctggcc cagctgagcc cccaggagcg tctgagccgg 600
gagacggccc tccagcagaa gcaggtgtct ctggaggcct ggttgcagcg tgaggcacag 660
acactgcagc agtaccgcgt ggagctggcc gagaagcacc agaagaccct gcagctgctg 720
cggaagcagc agaccatcat cctggatgac gagctgatcc agtggaagcg gcggcagcag 780
ctggccggga acggcgggcc ccccgagggc agcctggacg tgctacagtc ctggtgtgag 840
aagttggccg agatcatctg gcagaaccgg cagcagatcc gcagggctga gcacctctgc 900
cagcagctgc ccatccccgg cccagtggag gagatgctgg ccgaggtcaa cgccaccatc 960
acggacatta tctcagccct ggtgaccagc acattcatca ttgagaagca gcctcctcag 1020
gtcctgaaga cccagaccaa gtttgcagcc accgtacgcc tgctggtggg cgggaagctg 1080
aacgtgcaca tgaatccccc ccaggtgaag gccaccatca tcagtgagca gcaggccaag 1140
tctctgctta aaaatgagaa cacccgcaac gagtgcagtg gtgagatcct gaacaactgc 1200
tgcgtgatgg agtaccacca agccacgggc accctcagtg cccacttcag gaacatgtca 1260
ctgaagagga tcaagcgtgc tgaccggcgg ggtgcagagt ccgtgacaga ggagaagttc 1320
acagtcctgt ttgagtctca gttcagtgtt ggcagcaatg agcttgtgtt ccaggtgaag 1380
actctgtccc tacctgtggt tgtcatcgtc cacggcagcc aggaccacaa tgccacggct 1440
actgtgctgt gggacaatgc ctttgctgag ccgggcaggg tgccatttgc cgtgcctgac 1500
aaagtgctgt ggccgcagct gtgtgaggcg ctcaacatga aattcaaggc cgaagtgcag 1560
agcaaccggg gcctgaccaa ggagaacctc gtgttcctgg cgcagaaact gttcaacaac 1620
agcagcagcc acctggagga ctacagtggc ctgtccgtgt cctggtccca gttcaacagg 1680
gagaacttgc cgggctggaa ctacaccttc tggcagtggt ttgacggggt gatggaggtg 1740
ttgaagaagc accacaagcc ccactggaat gatggggcca tcctaggttt tgtgaataag 1800
caacaggccc acgacctgct catcaacaag cccgacggga ccttcttgtt gcgctttagt 1860
gactcagaaa tcgggggcat caccatcgcc tggaagtttg attccccgga acgcaacctg 1920
tggaacctga aaccattcac cacgcgggat ttctccatca ggtccctggc tgaccggctg 1980
ggggacctga gctatctcat ctatgtgttt cctgaccgcc ccaaggatga ggtcttctcc 2040
aagtactaca ctcctgtgct ggctaaagct gttgatggat atgtgaaacc acagatcaag 2100
caagtggtcc ctgagtttgt gaatgcatct gcagatgctg ggggcagcag cgccacgtac 2160
atggaccagg ccccctcccc agctgtgtgc ccccaggctc cctataacat gtacccacag 2220
aaccctgacc atgtactcga tcaggatgga gaattcgacc tggatgagac catggatgtg 2280
gccaggcacg tggaggaact cttacgccga ccaatggaca gtcttgactc ccgcctctcg 2340
ccccctgccg gtcttttcac ctctgccaga ggctccctct catga 2385
<210> 119
<211> 1725
<212> DNA
<213> 人类
<400> 119
atgtggactt ttctgggcat tgccactttc acctattttt ataagaagtt cggggacttc 60
atcactttgg ccaacaggga ggtcctgttg tgcgtgctgg tgttcctctc gctgggcctg 120
gtgctctcct accgctgtcg ccaccgaaac gggggtctcc tcgggcgcca gcagagcggc 180
tcccagttcg ccctcttctc ggatattctc tcaggcctgc ctttcattgg cttcttctgg 240
gccaaatccc cccctgaatc agaaaataag gagcagctcg aggccaggag gcgcagaaaa 300
ggaaccaata tttcagaaac aagcttaata ggaacagctg cctgtacatc aacatcttct 360
cagaatgacc cagaagttat catcgtggga gctggcgtgc ttggctctgc tttggcagct 420
gtgctttcca gagatggaag aaaggtgaca gtcattgaga gagacttaaa agagcctgac 480
agaatagttg gagaattcct gcagccgggt ggttatcatg ttctcaaaga ccttggtctt 540
ggagatacag tggaaggtct tgatgcccag gttgtaaatg gttacatgat tcatgatcag 600
gaaagcaaat cagaggttca gattccttac cctctgtcag aaaacaatca agtgcagagt 660
ggaagagctt tccatcacgg aagattcatc atgagtctcc ggaaagcagc tatggcagag 720
cccaatgcaa agtttattga aggtgttgtg ttacagttat tagaggaaga tgatgttgtg 780
atgggagttc agtacaagga taaagagact ggagatatca aggaactcca tgctccactg 840
actgttgttg cagatgggct tttctccaag ttcaggaaaa gcctggtctc caataaagtt 900
tctgtatcat ctcattttgt tggctttctt atgaagaatg caccacagtt taaagcaaat 960
catgctgaac ttattttagc taacccgagt ccagttctca tctaccagat ttcatccagt 1020
gaaactcgag tacttgttga cattagagga gaaatgccaa ggaatttaag agaatacatg 1080
gttgaaaaaa tttacccaca aatacctgat cacctgaaag aaccattctt agaagccact 1140
gacaattctc atctgaggtc catgccagca agcttccttc ctccttcatc agtgaagaaa 1200
cgaggtgttc ttcttttggg agacgcatat aatatgaggc atccacttac tggtggagga 1260
atgactgttg cttttaaaga tataaaacta tggagaaaac tgctaaaggg tatccctgac 1320
ctttatgatg atgcagctat tttcgaggcc aaaaaatcat tttactgggc aagaaaaaca 1380
tctcattcct ttgtcgtgaa tatccttgct caggctcttt atgaattatt ttctgccaca 1440
gatgattccc tgcatcaact aagaaaagcc tgttttcttt atttcaaact tggtggcgaa 1500
tgtgttgcgg gtcctgttgg gctgctttct gtattgtctc ctaaccctct agttttaatt 1560
ggacacttct ttgctgttgc aatctatgcc gtgtattttt gctttaagtc agaaccttgg 1620
attacaaaac ctcgagccct tctcagtagt ggtgctgtat tgtacaaagc gtgttctgta 1680
atatttcctc taatttactc agaaatgaag tatatggttc attaa 1725
<210> 120
<211> 1029
<212> DNA
<213> 人类
<400> 120
atggacctgt ggaactggga tgaggcatcc ccacaggaag tgcctccagg gaacaagctg 60
gcagggcttg aaggagccaa attaggcttc tgtttccctg atctggcact ccaaggggac 120
acgccgacag cgacagcaga gacatgctgg aaaggtacaa gctcatccct ggcaagcttc 180
ccacagctgg actggggctc cgcgttactg cacccagaag ttccatgggg ggcggagccc 240
gactctcagg ctcttccgtg gtccggggac tggacagaca tggcgtgcac agcctgggac 300
tcttggagcg gcgcctcgca gaccctgggc cccgcccctc tcggcccggg ccccatcccc 360
gccgccggct ccgaaggcgc cgcgggccag aactgcgtcc ccgtggcggg agaggccacc 420
tcgtggtcgc gcgcccaggc cgccgggagc aacaccagct gggactgttc tgtggggccc 480
gacggcgata cctactgggg cagtggcctg ggcggggagc cgcgcacgga ctgtaccatt 540
tcgtggggcg ggcccgcggg cccggactgt accacctcct ggaacccggg gctgcatgcg 600
ggtggcacca cctctttgaa gcggtaccag agctcagctc tcaccgtttg ctccgaaccg 660
agcccgcagt cggaccgtgc cagtttggct cgatgcccca aaactaacca ccgaggtccc 720
attcagctgt ggcagttcct cctggagctg ctccacgacg gggcgcgtag cagctgcatc 780
cgttggactg gcaacagccg cgagttccag ctgtgcgacc ccaaagaggt ggctcggctg 840
tggggcgagc gcaagagaaa gccgggcatg aattacgaga agctgagccg gggccttcgc 900
tactactatc gccgcgacat cgtgcgcaag agcggggggc gaaagtacac gtaccgcttc 960
gggggccgcg tgcccagcct agcctatccg gactgtgcgg gaggcggacg gggagcagag 1020
acacaataa 1029
<210> 121
<211> 1443
<212> DNA
<213> 人类
<400> 121
atggaggtgg cgcccgagca gccgcgctgg atggcgcacc cggccgtgct gaatgcgcag 60
caccccgact cacaccaccc gggcctggcg cacaactaca tggaacccgc gcagctgctg 120
cctccagacg aggtggacgt cttcttcaat cacctcgact cgcagggcaa cccctactat 180
gccaaccccg ctcacgcgcg ggcgcgcgtc tcctacagcc ccgcgcacgc ccgcctgacc 240
ggaggccaga tgtgccgccc acacttgttg cacagcccgg gtttgccctg gctggacggg 300
ggcaaagcag ccctctctgc cgctgcggcc caccaccaca acccctggac cgtgagcccc 360
ttctccaaga cgccactgca cccctcagct gctggaggcc ctggaggccc actctctgtg 420
tacccagggg ctgggggtgg gagcggggga ggcagcggga gctcagtggc ctccctcacc 480
cctacagcag cccactctgg ctcccacctt ttcggcttcc cacccacgcc acccaaagaa 540
gtgtctcctg accctagcac cacgggggct gcgtctccag cctcatcttc cgcggggggt 600
agtgcagccc gaggagagga caaggacggc gtcaagtacc aggtgtcact gacggagagc 660
atgaagatgg aaagtggcag tcccctgcgc ccaggcctag ctactatggg cacccagcct 720
gctacacacc accccatccc cacctacccc tcctatgtgc cggcggctgc ccacgactac 780
agcagcggac tcttccaccc cggaggcttc ctggggggac cggcctccag cttcacccct 840
aagcagcgca gcaaggctcg ttcctgttca gaaggccggg agtgtgtcaa ctgtggggcc 900
acagccaccc ctctctggcg gcgggacggc accggccact acctgtgcaa tgcctgtggc 960
ctctaccaca agatgaatgg gcagaaccga ccactcatca agcccaagcg aagactgtcg 1020
gccgccagaa gagccggcac ctgttgtgca aattgtcaga cgacaaccac caccttatgg 1080
cgccgaaacg ccaacgggga ccctgtctgc aacgcctgtg gcctctacta caagctgcac 1140
aatgttaaca ggccactgac catgaagaag gaagggatcc agactcggaa ccggaagatg 1200
tccaacaagt ccaagaagag caagaaaggg gcggagtgct tcgaggagct gtcaaagtgc 1260
atgcaggaga agtcatcccc cttcagtgca gctgccctgg ctggacacat ggcacctgtg 1320
ggccacctcc cgcccttcag ccactccgga cacatcctgc ccactccgac gcccatccac 1380
ccctcctcca gcctctcctt cggccacccc cacccgtcca gcatggtgac cgccatgggc 1440
tag 1443
<210> 122
<211> 915
<212> DNA
<213> 人类
<400> 122
atgaagcgag ctcaccccga gtacagctcc tcggacagcg agctggacga gaccatcgag 60
gtggagaagg agagtgcgga cgagaatgga aacttgagtt cggctctagg ttccatgtcc 120
ccaactacat cttcccagat tttggccaga aaaagacgga gaggaataat tgagaagcgc 180
cgacgagacc ggatcaataa cagtttgtct gagctgagaa ggctggtacc cagtgctttt 240
gagaagcagg gatctgctaa gctagaaaaa gccgagatcc tgcagatgac cgtggatcac 300
ctgaaaatgc tgcatacggc aggagggaaa ggttactttg acgcgcacgc ccttgctatg 360
gactatcgga gtttgggatt tcgggaatgc ctggcagaag ttgcgcgtta tctgagcatc 420
attgaaggac tagatgcctc tgacccgctt cgagttcgac tggtttcgca tctcaacaac 480
tacgcttccc agcgggaagc cgcgagcggc gcccacgcgg gcctcggaca cattccctgg 540
gggaccgtct tcggacatca cccgcacatc gcgcacccgc tgttgctgcc ccagaacggc 600
cacgggaacg cgggcaccac ggcctcaccc acggaaccgc accaccaggg caggctgggc 660
tcggcacatc cggaggcgcc tgctttgcga gcgcccccta gcggcagcct cggaccggtg 720
ctccctgtgg tcacctccgc ctccaaactg tcgccgcctc tgctctcctc agtggcctcc 780
ctgtcggcct tccccttctc tttcggctcc ttccacttac tgtctcccaa tgcactgagc 840
ccttcagcac ccacgcaggc tgcaaacctt ggcaagccct atagaccttg ggggacggag 900
atcggagctt tttaa 915
<210> 123
<211> 1014
<212> DNA
<213> 人类
<400> 123
atgaagcgcc cctgcgagga gacgacctcc gagagcgaca tggacgagac catcgacgtg 60
gggagcgaga acaattactc ggggcaaagt actagctctg tgattagatt gaattctcca 120
acaacaacat ctcagattat ggcaagaaag aaaaggagag ggattataga gaaaaggcgt 180
cgggatcgga taaataacag tttatctgag ttgagaagac ttgtgccaac tgcttttgaa 240
aaacaaggat ctgcaaagtt agaaaaagct gaaatattgc aaatgacagt ggatcatttg 300
aagatgcttc aggcaacagg gggtaaaggc tactttgacg cacacgctct tgccatggac 360
ttcatgagca taggattccg agagtgccta acagaagttg cgcggtacct gagctccgtg 420
gaaggcctgg actcctcgga tccgctgcgg gtgcggcttg tgtctcatct cagcacttgc 480
gccacccagc gggaggcggc ggccatgaca tcctccatgg cccaccacca tcatccgctc 540
cacccgcatc actgggccgc cgccttccac cacctgcccg cagccctgct ccagcccaac 600
ggcctccatg cctcagagtc aaccccttgt cgcctctcca caacttcaga agtgcctcct 660
gcccacggct ctgctctcct cacggccacg tttgcccatg cggattcagc cctccgaatg 720
ccatccacgg gcagcgtcgc cccctgcgtg ccacctctct ccacctctct cttgtccctc 780
tctgccaccg tccacgccgc agccgcagca gccaccgcgg ctgcacacag cttccctctg 840
tccttcgcgg gggcattccc catgcttccc ccaaacgcag cagcagcagt ggccgcggcc 900
acagccatca gcccgccctt gtcagtatca gccacgtcca gtcctcagca gaccagcagt 960
ggaacaaaca ataaacctta ccgaccctgg gggacagaag ttggagcttt ttaa 1014
<210> 124
<211> 1662
<212> DNA
<213> 人类
<400> 124
atgcaggcgc gctactccgt gtccagcccc aactccctgg gagtggtgcc ctacctcggc 60
ggcgagcaga gctactaccg cgcggcggcc gcggcggccg ggggcggcta caccgccatg 120
ccggccccca tgagcgtgta ctcgcaccct gcgcacgccg agcagtaccc gggcggcatg 180
gcccgcgcct acgggcccta cacgccgcag ccgcagccca aggacatggt gaagccgccc 240
tatagctaca tcgcgctcat caccatggcc atccagaacg ccccggacaa gaagatcacc 300
ctgaacggca tctaccagtt catcatggac cgcttcccct tctaccggga caacaagcag 360
ggctggcaga acagcatccg ccacaacctc tcgctcaacg agtgcttcgt caaggtgccg 420
cgcgacgaca agaagccggg caagggcagc tactggacgc tggacccgga ctcctacaac 480
atgttcgaga acggcagctt cctgcggcgg cggcggcgct tcaagaagaa ggacgcggtg 540
aaggacaagg aggagaagga caggctgcac ctcaaggagc cgcccccgcc cggccgccag 600
cccccgcccg cgccgccgga gcaggccgac ggcaacgcgc ccggtccgca gccgccgccc 660
gtgcgcatcc aggacatcaa gaccgagaac ggtacgtgcc cctcgccgcc ccagcccctg 720
tccccggccg ccgccctggg cagcggcagc gccgccgcgg tgcccaagat cgagagcccc 780
gacagcagca gcagcagcct gtccagcggg agcagccccc cgggcagcct gccgtcggcg 840
cggccgctca gcctggacgg tgcggattcc gcgccgccgc cgcccgcgcc ctccgccccg 900
ccgccgcacc atagccaggg cttcagcgtg gacaacatca tgacgtcgct gcgggggtcg 960
ccgcagagcg cggccgcgga gctcagctcc ggccttctgg cctcggcggc cgcgtcctcg 1020
cgcgcgggga tcgcaccccc gctggcgctc ggcgcctact cgcccggcca gagctccctc 1080
tacagctccc cctgcagcca gacctccagc gcgggcagct cgggcggcgg cggcggcggc 1140
gcgggggccg cggggggcgc gggcggcgcc gggacctacc actgcaacct gcaagccatg 1200
agcctgtacg cggccggcga gcgcgggggc cacttgcagg gcgcgcccgg gggcgcgggc 1260
ggctcggccg tggacgaccc cctgcccgac tactctctgc ctccggtcac cagcagcagc 1320
tcgtcgtccc tgagtcacgg cggcggcggc ggcggcggcg ggggaggcca ggaggccggc 1380
caccaccctg cggcccacca aggccgcctc acctcgtggt acctgaacca ggcgggcgga 1440
gacctgggcc acttggcgag cgcggcggcg gcggcggcgg ccgcaggcta cccgggccag 1500
cagcagaact tccactcggt gcgggagatg ttcgagtcac agaggatcgg cttgaacaac 1560
tctccagtga acgggaatag tagctgtcaa atggccttcc cttccagcca gtctctgtac 1620
cgcacgtccg gagctttcgt ctacgactgt agcaagtttt ga 1662
<210> 125
<211> 1506
<212> DNA
<213> 人类
<400> 125
atgcaggcgc gctactccgt gtccgacccc aacgccctgg gagtggtgcc ctacctgagc 60
gagcagaatt actaccgggc tgcgggcagc tacggcggca tggccagccc catgggcgtc 120
tattccggcc acccggagca gtacagcgcg gggatgggcc gctcctacgc gccctaccac 180
caccaccagc ccgcggcgcc taaggacctg gtgaagccgc cctacagcta catcgcgctc 240
atcaccatgg ccatccagaa cgcgcccgag aagaagatca ccttgaacgg catctaccag 300
ttcatcatgg accgcttccc cttctaccgg gagaacaagc agggctggca gaacagcatc 360
cgccacaacc tctcgctcaa cgagtgcttc gtcaaggtgc cccgcgacga caagaagccc 420
ggcaagggca gttactggac cctggacccg gactcctaca acatgttcga gaacggcagc 480
ttcctgcggc gccggcggcg cttcaaaaag aaggacgtgt ccaaggagaa ggaggagcgg 540
gcccacctca aggagccgcc cccggcggcg tccaagggcg ccccggccac cccccaccta 600
gcggacgccc ccaaggaggc cgagaagaag gtggtgatca agagcgaggc ggcgtccccg 660
gcgctgccgg tcatcaccaa ggtggagacg ctgagccccg agagcgcgct gcagggcagc 720
ccgcgcagcg cggcctccac gcccgccggc tcccccgacg gctcgctgcc ggagcaccac 780
gccgcggcgc ccaacgggct gcctggcttc agcgtggaga acatcatgac cctgcgaacg 840
tcgccgccgg gcggagagct gagcccgggg gccggacgcg cgggcctggt ggtgccgccg 900
ctggcgctgc cctacgccgc cgcgccgccc gccgcctacg gccagccgtg cgctcagggc 960
ctggaggccg gggccgccgg gggctaccag tgcagcatgc gagcgatgag cctgtacacc 1020
ggggccgagc ggccggcgca catgtgcgtc ccgcccgccc tggacgaggc cctctcggac 1080
cacccgagcg gccccacgtc gcccctgagc gctctcaacc tcgccgccgg ccaggagggc 1140
gcgctcgccg ccacgggcca ccaccaccag caccacggcc accaccaccc gcaggcgccg 1200
ccgcccccgc cggctcccca gccccagccg acgccgcagc ccggggccgc cgcggcgcag 1260
gcggcctcct ggtatctcaa ccacagcggg gacctgaacc acctccccgg ccacacgttc 1320
gcggcccagc agcaaacttt ccccaacgtg cgggagatgt tcaactccca ccggctgggg 1380
attgagaact cgaccctcgg ggagtcccag gtgagtggca atgccagctg ccagctgccc 1440
tacagatcca cgccgcctct ctatcgccac gcagccccct actcctacga ctgcacgaaa 1500
tactga 1506
<210> 126
<211> 1167
<212> DNA
<213> 人类
<400> 126
atggcttcgc tgctgggagc ctacccttgg cccgagggtc tcgagtgccc ggccctggac 60
gccgagctgt cggatggaca atcgccgccg gccgtccccc ggcccccggg ggacaagggc 120
tccgagagcc gtatccggcg gcccatgaac gccttcatgg tttgggccaa ggacgagagg 180
aaacggctgg cagtgcagaa cccggacctg cacaacgccg agctcagcaa gatgctggga 240
aagtcgtgga aggcgctgac gctgtcccag aagaggccgt acgtggacga ggcggagcgg 300
ctgcgcctgc agcacatgca ggactacccc aactacaagt accggccgcg caggaagaag 360
caggccaagc ggctgtgcaa gcgcgtggac ccgggcttcc ttctgagctc cctctcccgg 420
gaccagaacg ccctgccgga gaagagaagc ggcagccggg gggcgctggg ggagaaggag 480
gacaggggtg agtactcccc cggcactgcc ctgcccagcc tccggggctg ctaccacgag 540
gggccggctg gtggtggcgg cggcggcacc ccgagcagtg tggacacgta cccgtacggg 600
ctgcccacac ctcctgaaat gtctcccctg gacgtgctgg agccggagca gaccttcttc 660
tcctccccct gccaggagga gcatggccat ccccgccgca tcccccacct gccagggcac 720
ccgtactcac cggagtacgc cccaagccct ctccactgta gccaccccct gggctccctg 780
gcccttggcc agtcccccgg cgtctccatg atgtcccctg tacccggctg tcccccatct 840
cctgcctatt actccccggc cacctaccac ccactccact ccaacctcca agcccacctg 900
ggccagcttt ccccgcctcc tgagcaccct ggcttcgacg ccctggatca actgagccag 960
gtggaactcc tgggggacat ggatcgcaat gaattcgacc agtatttgaa cactcctggc 1020
cacccagact ccgccacagg ggccatggcc ctcagtgggc atgttccggt ctcccaggtg 1080
acaccaacgg gtcccacaga gaccagcctc atctccgtcc tggctgatgc cacggccacg 1140
tactacaaca gctacagtgt gtcatag 1167
<210> 127
<211> 1155
<212> DNA
<213> 人类
<400> 127
atgcagagat cgccgcccgg ctacggcgca caggacgacc cgcccgcccg ccgcgactgt 60
gcatgggccc cgggacacgg ggccgccgct gacacgcgcg gcctcgccgc cggccccgcc 120
gccctcgccg cgcccgccgc gcccgcctcg ccgcccagcc cgcagcgcag tcccccgcgc 180
agccccgagc cggggcgcta tggcctcagc ccggccggcc gcggggaacg ccaggcggca 240
gacgagtcgc gcatccggcg gcccatgaac gccttcatgg tgtgggcaaa ggacgagcgc 300
aagcggctgg ctcagcagaa cccggacctg cacaacgcgg tgctcagcaa gatgctgggc 360
aaagcgtgga aggagctgaa cgcggcggag aagcggccct tcgtggagga agccgaacgg 420
ctgcgcgtgc agcacttgcg cgaccacccc aactacaagt accggccgcg ccgcaagaag 480
caggcgcgca aggcccggcg gctggagccc ggcctcctgc tcccgggatt agcgcccccg 540
cagccaccgc ccgagccttt ccccgcggcg tctggctcgg ctcgcgcctt ccgcgagctg 600
cccccgctgg gcgccgagtt cgacggcctg gggctgccca cgcccgagcg ctcgcctctg 660
gacggcctgg agcccggcga ggctgccttc ttcccaccgc ccgcggcgcc cgaggactgc 720
gcgctgcggc ccttccgcgc gccctacgcg cccaccgagt tgtcgcggga ccccggcggt 780
tgctacgggg ctcccctggc ggaggcgctc aggaccgcgc cccccgcggc gccgctcgct 840
ggcctgtact acggcaccct gggcacgccc ggcccgtacc ccggcccgct gtcgccgccg 900
cccgaggccc cgccgctgga gagcgccgag ccgctggggc ccgccgccga tctgtgggcc 960
gacgtggacc tcaccgagtt cgaccagtac ctcaactgca gccggactcg gcccgacgcc 1020
cccgggctcc cgtaccacgt ggcactggcc aaactgggcc cgcgcgccat gtcctgccca 1080
gaggagagca gcctgatctc cgcgctgtcg gacgccagca gcgcggtcta ttacagcgcg 1140
tgcatctccg gctag 1155

Claims (3)

1.蛋白转导试剂修饰的重编程蛋白和额外的治疗剂用于制备用于在需要其的受试者中治疗胶质母细胞瘤或乳腺癌的药物的用途，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质，其中所述蛋白转导试剂修饰的重编程蛋白为：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog；其中所述蛋白转导试剂选自：QQ1a、QQ2a、QQ3a、QQ4a、QQ5a、QQ6a、QQ7a、QQ8a和QQ9a。
2.权利要求1的用途，其中所述额外的治疗剂是化合物、生物大分子、抗体或其组合。
3.蛋白转导试剂修饰的重编程蛋白用于制备用于在需要其的受试者中治疗胶质母细胞瘤或乳腺癌的药物的用途，其中所述蛋白转导试剂与所述重编程蛋白非共价结合并且其中所述蛋白转导试剂包含阳离子试剂和脂质，其中所述蛋白转导试剂修饰的重编程蛋白为：蛋白转导试剂修饰的Sox2、蛋白转导试剂修饰的Oct4和蛋白转导试剂修饰的Nanog；其中所述蛋白转导试剂选自：QQ1a、QQ2a、QQ3a、QQ4a、QQ5a、QQ6a、QQ7a、QQ8a和QQ9a，其中所述重编程蛋白是活性蛋白质或变性蛋白质。
CN202011127974.8A 2013-10-25 2014-10-27 与通过蛋白诱导的体内细胞重编程的细胞转化相关的方法、系统和组合物 Pending CN112245592A (zh)

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