CN108471732A - 与肿瘤分析相关的组合物和方法 - Google Patents
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Abstract
本发明提供了一种经遗传修饰的NOD.Cg‑PrkdcscidIl2rgtm1Wjl/SzJ小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白,其中所述突变的iRhom2蛋白由于一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型iRhom2蛋白不同,并且其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述小鼠的特征在于无毛表型和增加的外源肿瘤生长。
Description
相关专利申请的交叉引用
本申请要求于2015年10月30日提交的美国临时专利申请No.62/248,417的优先权,所述临时申请的全部内容以引用的方式纳入本文。
技术领域
根据具体的方面,本发明提供了经遗传修饰的NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG)小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白,其中所述突变的iRhom2蛋白由于一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型iRhom2蛋白不同,并且其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述小鼠的特征在于无毛表型和增加的外源肿瘤生长。
背景技术
尽管近年来已经在对癌症的诊断和治疗中取得了重大进展,但该疾病仍然是常见和普遍的。美国国立癌症研究所的监测流行病学和最终结果(SEER)数据库显示,根据2010年至2012年美国的发病率和死亡率数据,在美国1/2的男性和1/3的女性被认为处于发生某些类型的癌症的风险中。同一数据库显示,在美国1/4的男性和1/5的女性被认为处于因某些类型的癌症而死亡的风险中。
需要在癌症的诊断和治疗上取得进展来提高存活机率。然而,用于研究和评估癌症和新药的大多数癌症模型由体外细胞系组成,并且考虑到体内生理过程的复杂性,对这种体外模型的分析可能具有有限的价值。目前的体内癌症模型在应用中经常受到限制,特别是在需要尽可能快地进行分析(例如对在体内生长的异种移植肿瘤中的来自患者的肿瘤细胞的分析)的情况下。
因此,持续需要用于鉴定抗肿瘤组合物的体内癌症模型和方法以及使用所述体内癌症模型进行治疗的方法。
发明内容
根据本发明的方面,提供了一种经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长。
根据本发明的方面,提供了一种经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长,并且其中所述经遗传修饰的NSG小鼠包括异种肿瘤细胞。
根据本发明的方面,提供了一种经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长,并且其中所述经遗传修饰的NSG小鼠包括获自人类受试者的肿瘤的异种肿瘤细胞。
根据本发明的方面,提供了经遗传修饰的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠。根据本发明的方面,提供了经遗传修饰的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,其包括异种肿瘤细胞。根据本发明的方面,提供了经遗传修饰的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,其包括获自人类受试者的肿瘤的异种肿瘤细胞。
根据各方面,本发明提供了一种产生用于评估异种肿瘤细胞的小鼠模型系统的方法,所述方法包括提供经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于iRhom2的N-末端区域中的一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供异种肿瘤细胞;以及将所述异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,由此产生用于评估异种肿瘤细胞的小鼠模型系统。
根据各方面,本发明提供了一种产生用于评估获自人类受试者的肿瘤的异种肿瘤细胞的小鼠模型系统的方法,所述方法包括提供经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得小鼠表达突变的iRhom2蛋白——其由于iRhom2的N-末端区域中的一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供获自人类受试者的肿瘤的异种肿瘤细胞;以及将所述异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,由此产生用于评估获自人类受试者的肿瘤的异种肿瘤细胞的小鼠模型系统。
根据各方面,本发明提供了一种产生用于评估异种肿瘤细胞的小鼠模型系统的方法,所述方法包括提供NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供异种肿瘤细胞;以及将所述异种肿瘤细胞给予至所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,由此产生用于评估异种肿瘤细胞的小鼠模型系统。
根据各方面,本发明提供了一种产生用于评估异种肿瘤细胞的小鼠模型系统的方法,所述方法包括提供NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供获自人类受试者的肿瘤的异种肿瘤细胞;以及将所述异种肿瘤细胞给予至所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,由此产生用于评估异种肿瘤细胞的小鼠模型系统。
根据各方面,本发明提供了一种鉴定抗肿瘤组合物的方法,所述方法包括提供经遗传修饰的NSG小鼠,其中所述小鼠的基因组包含突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和pP 159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供异种肿瘤细胞;将所述异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,产生了包括异种肿瘤细胞的经遗传修饰的NSG小鼠;将测试物质给予至所述包括异种肿瘤细胞的经遗传修饰的NSG小鼠;在将所述测试物质给予至所述包括异种肿瘤细胞的经遗传修饰的NSG小鼠后,测定异种肿瘤细胞对所述测试物质的反应;以及将所述反应与标准进行比较以确定所述测试物质对所述异种肿瘤细胞的作用,其中所述测试物质对所述异种肿瘤细胞的抑制作用将所述测试物质鉴定为抗肿瘤组合物。
根据各方面,本发明提供了一种鉴定抗肿瘤组合物的方法,所述方法包括提供经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于iRhom2的N-末端区域中的一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供获自人类受试者的肿瘤的异种肿瘤细胞;将所述获自人类受试者的肿瘤的异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,产生了包括获自人类受试者的肿瘤的异种肿瘤细胞的经遗传修饰的NSG小鼠;将测试物质给予至具有所给予的获自人类受试者的肿瘤的异种肿瘤细胞的所述经遗传修饰的NSG小鼠;在将所述测试物质给予至所述包括获自人类受试者的肿瘤的异种肿瘤细胞的经遗传修饰的NSG小鼠后,测定小鼠中获自人类受试者的肿瘤的异种肿瘤细胞对所述测试物质的反应;以及将所述反应与标准进行比较以确定所述测试物质对获自人类受试者的肿瘤的异种肿瘤细胞的作用,其中所述测试物质对获自人类受试者的肿瘤的异种肿瘤细胞的抑制作用将所述测试物质鉴定为抗肿瘤组合物。
根据各方面,本发明提供了一种鉴定抗肿瘤组合物的方法,所述方法包括提供NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供异种肿瘤细胞;将所述异种肿瘤细胞给予至所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,产生了包括异种肿瘤细胞的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠;将测试物质给予至所述包括异种肿瘤细胞的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠;在将所述测试物质给予至所述包括异种肿瘤细胞的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠后,测定异种肿瘤细胞对所述测试物质的反应;以及将所述反应与标准进行比较以确定所述测试物质对异种肿瘤细胞的作用,其中所述测试物质对异种肿瘤细胞的抑制作用将所述测试物质鉴定为抗肿瘤组合物。
根据各方面,本发明提供了一种鉴定抗肿瘤组合物的方法,所述方法包括提供NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠的特征在于无毛表型和增加的异种肿瘤生长;提供获自人类受试者的肿瘤的异种肿瘤细胞;将所述获自人类受试者的肿瘤的异种肿瘤细胞给予至所述NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠,产生了包括获自人类受试者的肿瘤的异种肿瘤细胞的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠;将测试物质给予至所述包括获自人类受试者的肿瘤的异种肿瘤细胞的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠;在将所述测试物质给予至所述包括获自人类受试者的肿瘤的异种肿瘤细胞的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠后,测定获自人类受试者的肿瘤的异种肿瘤细胞对所述测试物质的反应;以及将所述反应与标准进行比较以确定所述测试物质对获自人类受试者的肿瘤的异种肿瘤细胞的作用,其中所述测试物质对获自人类受试者的肿瘤的异种肿瘤细胞的抑制作用将所述测试物质鉴定为抗肿瘤组合物。
附图说明
图1示出了小鼠iRhom2(SEQ ID NO:1)的示意图,其示出了N-末端区域(第1-373位氨基酸)和C-末端区域(第374-827位氨基酸)并且指示了第159位氨基酸的相对位置;
图2A是DNA测序仪器的图形输出,其示出了与编码p.P159L突变iRhom2(第159位氨基酸处(下部,箭头))的小鼠p.P159L突变Rhbdf2基因的区域的DNA测序结果相比,编码iRhom2(第159位氨基酸处(上部,箭头))的小鼠野生型(WT)Rhbdf2基因的区域的DNA测序结果;
图2B是DNA测序仪器的图形输出,其示出了对编码在第156位氨基酸处密码子由ATT(野生型)突变为ACT(加阴影的C)的p.I156T突变iRhom2的小鼠p.I156T突变Rhbdf2基因的区域的DNA测序结果;
图2C是DNA测序仪器的图形输出,其示出了对编码在第158位氨基酸处密码子由GAT(野生型)突变为AAT(箭头)的p.D158N突变iRhom2的小鼠p.D158N突变Rhbdf2基因的区域的DNA测序结果;
图3是携带Rhbdf2p.P159L突变(NSG-Bald)并以无毛表型为特征的6周龄小鼠(左)和携带野生型Rhbdf2等位基因的正常白毛同窝幼仔对照小鼠(右)的图像;
图4是示出了携带Rhbdf2p.P159L突变(NSG-Bald)并且表达在N-末端区域具有p.P159L突变的iRhom2的NSG小鼠中增加的异种肿瘤生长的图;
图5A是一组示出了对NSG小鼠中MDA-MB 231人乳腺癌细胞衍生的肿瘤的血管标记物CD31的免疫染色结果的图像;
图5B是一组示出了对表达在N-末端区域具有突变的iRhom2的小鼠中MDA-MB 231人乳腺癌细胞衍生的肿瘤的血管标记物CD31的免疫染色结果的图像;
图6是对小鼠iRhom1和iRhom2氨基酸序列的比较;
图7是示出了Rhbdf1基因缺失杂合型(Rhbdf1+/-)的小鼠的尺寸正常(右)和Rhbdf1基因缺失纯合型(Rhbdf1-/-)的小鼠的尺寸较小(左)的图像;
图8是示出了Rhbdf1基因缺失杂合型(Rhbdf1+/-)的小鼠表现出正常的存活百分数(上面的线),而Rhbdf1基因缺失纯合型(Rhbdf1-/-)的小鼠至3-4周龄时死亡(下面的线)的图;
图9是一组从具有导致在约3-4周龄时死亡的严重心脏纤维化(用“O”标记)的Rhbdf1-/-纯合型小鼠分离的心脏的经苏木精和伊红染色的切片的三个图像,比例尺为1mm;和
图10是从显示无心脏纤维化的Rhbdf1-/+杂合型小鼠分离的心脏的经苏木精和伊红染色的切片的图像,比例尺为1mm。
具体实施方式
菱形蛋白(rhomboid protein)几乎存在于所有物种中。菱形蛋白酶是负责对细胞调控而言很重要的裂解事件的膜内丝氨酸蛋白酶。这些膜内蛋白酶的活性位点埋在细胞膜的脂双层中,并且它们在其他跨膜蛋白的跨膜结构域内裂解这些蛋白。
无活性菱形蛋白酶(iRhom)是高度保守的膜内蛋白,其之前被认为不具有蛋白水解活性。野生型iRhom的特征在于胞质N-末端结构域、保守的富含半胱氨酸的无活性菱形蛋白酶同源结构域(IRHD)和在肽酶域内缺少活性位点丝氨酸残基的休眠的(dormant)蛋白水解位点。
在许多物种中,iRhom参与多种功能,包括在黑腹果蝇(Drosophilamelanogaster)中表皮生长因子受体(EGFR)信号传导的调节、人鳞状上皮癌细胞的存活、在哺乳动物细胞系中错误折叠的蛋白从内质网膜上的清除、原代小鼠角化细胞的迁移的诱导、在小鼠中可溶性TNFα的分泌、以及在小鼠胚胎成纤维细胞中受激的ADAM17介导的金属蛋白酶脱落(shedding)的底物选择性的调节。EGF样配体可作为iRhom家族成员的底物发挥作用。
iRhom功能的其他方面正在不断被阐明。如Mcflwain et al,Science,2012,335(6065):229-232中所述,发现iRhom2敲除小鼠是“可存活的和可育的、没有明显的缺陷、具有正常的寿命并且表现出正常的免疫细胞分布”。
令人惊讶的是,根据本文所述的本发明的方面,发现一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变导致NSG小鼠中的无毛表型和增加的异种肿瘤生长。NSG小鼠可用于研究多种类型的异种移植物,但它们的特征在于非常缓慢的异种肿瘤生长,并且由于覆盖异种肿瘤的皮肤上的毛发而难以对异种肿瘤进行成像,使得这些表型提供了显著的优势,这有助于开发人类以及其他哺乳动物中的抗肿瘤药物和治疗。
因此,本发明提供了经遗传修饰的免疫缺陷小鼠,其中所述免疫缺陷小鼠的基因组包括突变的Rhbdf2基因,以使得所述经遗传修饰的免疫缺陷小鼠表达突变的iRhom2蛋白,其中所述突变的iRhom2蛋白由于一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变而与野生型iRhom2蛋白不同,并且其中所述经遗传修饰的免疫缺陷小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
本发明的经遗传修饰的免疫缺陷小鼠、方法和组合物具有多种用途,例如但不限于,异种肿瘤细胞生长的模型、测定移植的异种肿瘤对药物和/或治疗性处理的反应的体内方法、测试影响先天免疫系统的试剂和测试影响与iRhom2相关的信号传导和活性的试剂。
本文使用的科技术语旨在具有本领域普通技术人员通常所理解的含义。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 and D.W.Russell,Molecular Cloning:A Laboratory Manual,Cold SpringHarbor Laboratory Press;第3版,2001;F.M.Ausubel,Ed.,Short Protocols inMolecular Biology,Current Protocols;第5版,2002;B.Alberts et al.,MolecularBiology of the Cell,第4版,Garland,2002;D.L.Nelson and M.M.Cox,LehningerPrinciples of Biochemistry,第4版,W.H.Freeman&Company,2004;Herdewijn,P.(Ed.),Oligonucleotide Synthesis:Methods and Applications,Methods in MolecularBiology,Humana Press,2004;A.Nagy,M.Gertsenstein,K.Vintersten,R.Behringer(Eds)2002,Manipulating the Mouse Embryo:A Laboratory Manual,第3版,Cold SpringHarbor Laboratory Press,ISBN-10:0879695919;和K.Turksen(Ed.),Embryonic stemcells:methods and protocols in Methods Mol Biol.2002;185,Humana Press;CurrentProtocols in Stem Cell Biology,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”、“一个”和“所述”不意为限制性的,且包括复数指代物。
本文使用的术语“核酸”是指具有多于一个核苷酸的RNA或DNA分子,其为任何形式,包括单链、双链的寡核苷酸或多聚核苷酸。术语“核苷酸序列”用于指在核酸的单链形式中寡核苷酸或多聚核苷酸中的核苷酸的排序。
术语“双链体”和“双链”用于指以互补核苷酸序列的结合相互作用为特征的核酸。双链体包括“有义”链和“反义”链。这种双链体包括RNA/RNA、DNA/DNA或RNA/DNA类型的双链体。
术语“寡核苷酸”在本文用于描述具有2-1000个连接的核苷酸的核苷酸序列,而术语“多聚核苷酸”用于描述具有多于1000个核苷酸的核苷酸序列。
术语“核苷酸”在本文用作名词来指代与核苷酸序列相对的单个核苷酸或核苷酸变体。
本文使用的术语“遗传工程小鼠”是指含有一个或多个通过分子生物学技术(即重组DNA技术)被引入到个体小鼠基因组或小鼠品系基因组中的DNA修饰的小鼠。术语“遗传工程小鼠”包括含有一个或多个被引入到个体小鼠基因组中的DNA修饰的小鼠的后代,其中所述后代也含有所述一个或多个DNA修饰。
术语“野生型”是指未突变的小鼠、蛋白或核酸。
小鼠野生型Rhbdf2基因编码无活性的菱形蛋白酶iRhom2,其含有胞质N-末端区域(第1-347位氨基酸)、保守的同源结构域和休眠的肽酶结构域。
野生型小鼠iRhom2蛋白具有在本文示为SEQ ID NO:1的氨基酸序列,其由野生型Rhbdf2基因序列SEQ ID NO:2编码。
野生型小鼠iRhom1蛋白具有在本文示为SEQ ID NO:3的氨基酸序列。
术语“表达(expression、expressing和expresses)”和语法上的同义词是指产生相应的mRNA的基因的转录和/或产生相应的蛋白的mRNA的翻译。用于突变的Rhbdf2基因的术语“表达(express、expression、expressing和expresses)”是指产生相应的mRNA的突变Rhbdf2基因的转录和/或产生相应的突变iRhom2蛋白的mRNA的翻译。
在本发明的具体方面,将突变引入到免疫缺陷小鼠的Rhbdf2基因中,产生特征在于表达突变的iRhom2蛋白的遗传工程免疫缺陷小鼠——其中所述突变的iRhom2蛋白由于一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变而与野生型iRhom2蛋白不同,并且与表达野生型iRhom2蛋白的相同遗传背景的免疫缺陷小鼠相比,所述遗传工程免疫缺陷小鼠的特征还在于无毛表型和增加的异种肿瘤生长。
本文使用的术语“无毛表型”是指表达在N-末端区域具有一个或多个突变的iRhom2蛋白的遗传工程免疫缺陷小鼠,其中与表达野生型iRhom2的相同遗传背景的小鼠相比,所述遗传工程免疫缺陷小鼠具有95%或更少的毛发。根据具体的方面,与表达野生型iRhom2的相同遗传背景的小鼠相比,表达具有一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变的iRhom2蛋白的遗传工程NSG小鼠具有95%或更少的毛发。
本文使用的术语“增加的异种肿瘤生长”是指表达在N-末端区域具有一个或多个突变的iRhom2蛋白的遗传工程免疫缺陷小鼠的特征,其中与表达相应野生型iRhom2的相同遗传背景的小鼠中的异种肿瘤相比,所述遗传工程免疫缺陷小鼠中的异种肿瘤体积增加得更快。根据具体方面,与表达野生型iRhom2的相同遗传背景的小鼠相比,表达具有一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变的iRhom2蛋白的遗传工程NSG小鼠的特征在于增加的异种肿瘤生长。术语“免疫缺陷小鼠”是指特征在于如下中的一种或多种的小鼠:缺乏功能性免疫细胞,如T细胞和B细胞;DNA修复缺陷;编码淋巴细胞上抗原特异性受体的基因的重排中的缺陷;和缺乏免疫功能分子如IgM、IgG1、IgG2a、IgG2b、IgG3和IgA。免疫缺陷小鼠的特征可以在于参与免疫功能的基因如Rag1和Rag2的一个或多个缺陷(Oettinger,M.Aet al.,Science,248:1517-1523,1990;和Schatz,DG et al.,Cell,59:1035-1048,1989)。免疫缺陷小鼠可具有导致小鼠中的免疫功能异常的任何这些或其他缺陷。
特别有用的免疫缺陷小鼠品系为NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ,其通常被称为NOD scid gamma(NSG)小鼠,详细记载在Shultz LD et al,2005,J.Immunol,174:6477-89中;NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ,Shultz LD et al,2008Clin Exp Immunol 154(2):270-84,其通常被称为NRG小鼠;和NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac,其通常被称为NOG小鼠,详细记载在Ito,M.et al.,Blood 100,3175-3182(2002)中。
术语“NOD scid gamma”和“NSG”在本文中可互换使用以指公知的免疫缺陷小鼠品系NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ。NSG小鼠结合了来自NOD/ShiLtJ背景的多种免疫缺陷、严重联合免疫缺陷(scid)突变和白细胞介素-2受体γ链的完全敲除。因此,NSG小鼠缺乏成熟的T、B和NK细胞,并且缺乏细胞因子信号传导。NSG小鼠的特征在于缺乏IL2R-γ(γc)表达、没有可检测的血清免疫球蛋白、没有溶血补体、没有成熟的T淋巴细胞、并且没有成熟的自然杀伤细胞。
术语“严重联合免疫缺陷(SCID)”是指以缺乏T细胞和缺乏B细胞功能为特征的病症。
SCID的常见形式包括:X连锁的SCID,其特征在于IL2RG基因中的γ链基因突变和淋巴细胞表型T(-)B(+)NK(-);和常染色体隐性SCID,其特征在于Jak3基因突变和淋巴细胞表型T(-)B(+)NK(-)、ADA基因突变和淋巴细胞表型T(-)B(-)NK(-)、IL-7Rα-链突变和淋巴细胞表型T(-)B(+)NK(+)、CD3δ或ε突变和淋巴细胞表型T(-)B(+)NK(+)、RAG1/RAG2突变和淋巴细胞表型T(-)B(-)NK(+)、Artemis基因突变和淋巴细胞表型T(-)B(-)NK(+)、CD45基因突变和淋巴细胞表型T(-)B(+)NK(+)。
根据本发明的方面的经遗传修饰的免疫缺陷小鼠具有严重联合免疫缺陷突变(Prkdcscid),其通常被称为scid突变。所述scid突变是公知的并且位于小鼠的第16号染色体上,如Bosma et al.,Immunogenetics29:54-56中所述。Scid突变纯合型的小鼠的特征在于缺乏功能性T细胞和B细胞、淋巴细胞减少、低球蛋白血症和正常造血微环境。可通过例如使用公知的方法(如PCR或流式细胞术)检测scid突变的标记物来检测scid突变。
根据本发明的方面的经遗传修饰的免疫缺陷小鼠具有IL2受体γ链缺陷。术语“IL2受体γ链缺陷”是指减少的IL2受体γ链。减少的IL2受体γ链可能是由于基因缺失或突变造成的。例如,可通过使用公知的方法检测IL2受体γ链基因缺失或突变和/或检测减少的IL2受体γ链表达来检测减少的IL2受体γ链。
根据本发明的方面,提供了具有严重联合免疫缺陷或具有IL2受体γ链缺陷和严重联合免疫缺陷的经遗传修饰的免疫缺陷小鼠,其基因组包括突变的Rhbdf2基因。
根据本发明的方面,提供了具有scid突变或具有IL2受体γ链缺陷和scid突变的经遗传修饰的免疫缺陷小鼠,其基因组包括突变的Rhbdf2基因,以使得小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变而与野生型iRhom2蛋白不同,并且其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了具有scid突变或具有IL2受体γ链缺陷和scid突变的经遗传修饰的免疫缺陷小鼠,其基因组包括突变的Rhbdf2基因,以使得小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变而与野生型iRhom2蛋白不同,并且其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了经遗传修饰的NSG小鼠,其基因组包括突变的Rhbdf2基因,以使得小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的小鼠iRhom2突变而与野生型iRhom2蛋白不同,并且其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
Rhbdf2基因的“突变”是指基因的遗传修饰,以使得具有Rhbdf2基因突变的小鼠表达由于N-末端区域中的一个或多个突变而与野生型iRhom2蛋白不同的突变iRhom2蛋白,并且其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,经遗传修饰的免疫缺陷小鼠包括突变的Rhbdf2基因,以使得所述经遗传修饰的免疫缺陷小鼠表达突变的iRhom2蛋白——其由于从SEQ ID NO:1的第1-373位氨基酸延伸的N-末端区域的至少一部分的框内缺失而与野生型iRhom2蛋白不同,并且其中所述经遗传修饰的免疫缺陷小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。突变的iRhom2的第374-827位氨基酸与SEQ ID NO:1的野生型iRhom2蛋白相同或基本相似。
根据本发明的方面,经遗传修饰的NSG小鼠包括突变的Rhbdf2基因,以使得所述经遗传修饰的NSG小鼠表达突变的iRhom2蛋白——其由于从SEQ ID NO:1的第1-373位氨基酸延伸的N-末端区域的至少一部分的框内缺失而与野生型iRhom2蛋白不同,并且其中所述经遗传修饰的免疫缺陷小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。突变的iRhom2的第374-827位氨基酸与SEQ ID NO:1的野生型iRhom2蛋白相同或基本相似。
用于SEQ ID NO:1的野生型iRhom2蛋白的第374-827位氨基酸的术语“基本相似”是指具有70%、75%、80%、81%、82%83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或更大的同一性,同时保留野生型iRhom2的第374-827位氨基酸的功能的氨基酸序列。
根据本发明的方面,所述经遗传修饰的免疫缺陷小鼠包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于在N-末端区域中的氨基酸第156位异亮氨酸、第158位天冬氨酸和第159位脯氨酸处的一个、两个或三个突变而与SEQ ID NO:1的野生型iRhom2蛋白不同,其中所述突变的iRhom2的第374-827位氨基酸与SEQ ID NO:1的野生型iRhom2蛋白相同或基本相似,并且其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
选自iRhom2的第156位异亮氨酸、第158位天冬氨酸和第159位脯氨酸的一个、两个或三个氨基酸可通过遗传修饰小鼠Rhbdf2基因而被突变为任意其他氨基酸或被缺失,以产生具有突变的Rhbdf2基因的经遗传修饰的免疫缺陷小鼠,其中所述小鼠表达具有选自p.I156T、p.D158N和p.P159L的一个或多个小鼠iRhom2突变的突变iRhom2蛋白,其中所述突变的iRhom2的第374-827位氨基酸与SEQ ID NO:1的野生型iRhom2蛋白相同或基本相似,并且其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,编码iRhom2的Rhbdf2基因序列的密码子156从ATT(野生型)突变为ACT或密码子的其他置换或缺失,以使得开放阅读框完整。
根据本发明的方面,编码iRhom2的Rhbdf2基因序列的密码子158从GAT突变为AAT或AAC或密码子的其他置换或缺失,以使得开放阅读框完整。
根据本发明的方面,编码iRhom2的Rhbdf2基因序列的密码子159从CCA突变为CTA或密码子的其他置换或缺失,以使得开放阅读框完整。
应理解,由于遗传密码的简并性质,多于一条的核酸序列编码特定的iRhom2多肽,并且这样的核酸序列可产生所需的iRhom2。
根据本发明的方面,提供了其基因组包括突变的Rhbdf2基因的经遗传修饰的NSG小鼠,其是具有突变(在第159位脯氨酸处)的Rhbdf2基因的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ(NSG-BALDP159L)小鼠,其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了其基因组包括突变的Rhbdf2基因的经遗传修饰的NSG小鼠,其是具有突变(在第159位脯氨酸处)的Rhbdf2基因的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159X/SzJ(NSG-BALDP159X)小鼠,其中X是任意氨基酸,其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了其基因组包括突变的Rhbdf2基因的经遗传修饰的NSG小鼠,其是具有突变(在第156位异亮氨酸处)的Rhbdf2基因的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfI156T/SzJ(NSG-BALDI156T)小鼠,其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了其基因组包括突变的Rhbdf2基因的经遗传修饰的NSG小鼠,其是具有突变(在第156位异亮氨酸处)的Rhbdf2基因的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfI156X/SzJ(NSG-BALDI156X)小鼠,其中X是任意氨基酸,其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了其基因组包括突变的Rhbdf2基因的经遗传修饰的NSG小鼠,其是具有突变(在第158位天冬氨酸处)的Rhbdf2基因的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfD158N/SzJ(NSG-BALDD158N)小鼠,其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
根据本发明的方面,提供了其基因组包括突变的Rhbdf2基因的经遗传修饰的NSG小鼠,其是具有突变(在第158位天冬氨酸处)的Rhbdf2基因的NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfD158X/SzJ(NSG-BALDD158X)小鼠,其中X是任意氨基酸,其中所述小鼠的特征在于无毛表型和增加的异种肿瘤细胞的生长。
虽然特别引用选自p.I156T、p.D158N和p.P159L的一个或多个小鼠iRhom2突变对本发明的经遗传修饰的小鼠及其用途的方面进行了描述,但考虑到了iRhom2的N-末端区域中的一个或多个不同或额外的突变,并且旨在涵盖落入本公开内容和权利要求的精神和广泛范围内的所有这类替代、修改和变化。
可使用多种方法中的任一种来突变Rhbdf2基因以产生经遗传修饰的免疫缺陷小鼠,其基因组包括Rhbdf2基因的突变。根据遗传工程的标准方法(例如但不限于基因组编辑、化学诱变、辐射、同源重组和反义RNA的转基因表达)在经遗传修饰的免疫缺陷小鼠的基因组中突变Rhbdf2基因。
用于产生其基因组包括突变基因的经遗传修饰的动物的方法包括但不限于如下中记载的那些:J.P.Sundberg and T.Ichiki,Eds.,Genetically Engineered MiceHandbook,CRC Press;2006;M.H.Hofker and J.van Deursen,Eds.,Transgenic MouseMethods and Protocols,Humana Press,2002;A.L.Joyner,Gene Targeting:A PracticalApproach,Oxford University Press,2000;Manipulating the Mouse Embryo:ALaboratory Manual,第3版,Cold Spring Harbor Laboratory Press;December 15,2002,ISBN-10:0879695919;Kursad Turksen(Ed.),Embryonic stem cells:methods andprotocols in Methods Mol Biol.2002;185,Humana Press;Current Protocols in StemCell Biology,ISBN:978047015180;Meyer et al.,PNAS USA,第107(34)卷,15022-15026。
遗传修饰方法
可使用基于同源性的重组基因修饰策略,例如归巢内切核酸酶,整合酶,大范围核酸酶,转座子,使用锌指核酸酶(ZFN)、转录激活因子样(TAL)、成簇的规律间隔的短回文重复序列(CRISPR)-Cas或果蝇重组相关蛋白(DRAP)方法的核酸酶介导的方法。简言之,所述方法包括将编码靶向TALEN或ZFN或CRISPR或DRAP的RNA分子和至少一种寡核苷酸引入到ES或iPS细胞中,然后选择具有经修正的基因的ES或iPS细胞。
基因的突变可直接在受精的卵母细胞(合子)或胚胎中完成。为此,可应用归巢内切核酸酶,整合酶,大范围核酸酶,转座子,核酸酶介导的方法,如锌指核酸酶、TALEN、CRISPR-Cas或DRAP。优选的方法是TALEN、ZFN、CRISPR-Cas或DRAP。简言之,所述方法包括将至少一种编码靶向TALEN、ZFN、CRISPR-Cas或DRAP的核酸分子和至少一种寡核苷酸引入到受精的卵母细胞或胚胎或细胞中。所述方法还包括孵育经受精的卵母细胞、胚胎或细胞以允许表达TALEN、ZFN、CRISPR-Cas或DRAP,其中通过TALEN、ZFN、CRISPR-Cas或DRAP引入至靶染色体序列的双链断裂通是过同源介导的DNA修复过程进行修复。编码TALEN、ZFN、CRISPR-Cas或DRAP的核酸可以是DNA(作为表达载体)或RNA。代替编码TALEN、ZFN、CRISPR-Cas或DRAP的核酸,可将TALEN、ZFN、CRISPR-Cas或DRAP蛋白递送至经受精的卵母细胞或胚胎或细胞中。DRAP技术已在US6534643、US6858716和US6830910以及Watt et al.,2006中记载。
本文使用的术语“靶位点”和“靶序列”是指限定待编辑的染色体序列的一部分并且核酸酶被改造以对其进行识别和结合(只要存在足够的结合条件)的核酸序列。
核酸酶
被改造以特异性结合靶位点的核酸酶(包括TALEN、ZFN和归巢内切核酸酶(如I-SceI))已被成功用于多种不同物种中的基因组修饰。
TAL(转录激活因子样)效应物
已知黄单胞杆菌属(Xanthomonas)的植物致病菌在重要的作物植物中引起许多疾病。黄单胞杆菌的致病性取决于保守性的III型分泌(T3S)系统,其将25种以上的不同的效应蛋白注入到植物细胞中。在这些经注入的蛋白中有转录激活因子样(TAL)效应物或TALE(转录激活因子样效应物),其模拟植物转录激活因子并操纵植物转录物,参见Kay et al.,2007,Science,318:648-651。这些蛋白含有DNA结合结构域和转录激活结构域。最充分表征的TAL-效应物之一是来自通用型番茄疮痂病辣椒斑点病菌(Xanthomonas campestrispv.vesicatoria)的AvrBs3(参见Bonas et al.,1989,Mol Gen Genet 218:127-136和WO2010079430)。TAL效应物含有串联重复序列的中央结构域,每个重复序列含有约34个氨基酸,其对于这些蛋白的DNA结合特异性来说是关键的。此外,它们含有核定位序列和酸性转录激活结构域,综述参见Schornack et al.2006,J Plant PhysioI163(3):256-272;Scholze and Boch 2011,Curr Opin Microbiol,14:47-53。此外,在植物病原菌青枯雷尔氏菌(Ralstonia solanacearum)中,被命名为brg11和hpx17的两个基因已在青枯雷尔氏菌生物变种1菌株GMI 1000和生物变种4菌株RS1000中被发现,这两个基因与黄单胞杆菌属的AvrBs3家族同源,参见Heuer et al.,2007,Appl and Envir Micro 73(13):4379-4384。这些基因在核苷酸序列上彼此98.9%相同,但区别在于hpxl7的重复序列结构域中的1,575bp的缺失。但是,这两种基因产物与黄单胞杆菌属的AvrBs3家族蛋白具有小于40%的序列同一性。
这些TAL效应物的特异性取决于存在于串联重复序列中的序列。所述重复序列包括约102bp,并且所述重复序列通常彼此91-100%同源(Bonas et al.,1989,Mol GenGenet 218:127-136)。所述重复序列的多态性通常位于第12和13位,并且在第12和13位的高变双残基的种类与TAL-效应物的靶序列中的连续核苷酸的种类之间似乎存在一对一的对应关系,参见Moscou and Bogdanove 2009,Science 326:1501;和Boch et al.,2009,Science 326:1509-1512。所述两个高变残基被称为重复可变双残基(RVD),由此一个RVD识别DNA序列的一个核苷酸,并确保每个TAL-效应物的DNA结合结构域可以高精度(15-30nt)靶向大的识别位点。在实验上,已经确定了这些TAL-效应物的DNA识别密码,使得第12和13位的HD序列导致与胞嘧啶(C)的结合,NG与T结合,NI与A、C、G或T结合,NN与A或G结合,并且IG与T结合。这些DNA结合重复序列已被组装成具有新的重复序列的组合和数目的蛋白,以制备人工转录因子,其能够与新序列相互作用并在植物细胞中激活报告基因的表达(Bochet al.,2009,Science 326:1509-1512)。现已证明这些DNA结合结构域在所有细胞类型中在靶向基因组编辑或靶向基因调控领域都中具有普遍适用性(Gaj et al.,2013)。此外,已证明经改造的TAL效应物与外源功能性蛋白效应物结构域(例如非天然存在于天然黄单胞杆菌TAL效应中或哺乳动物细胞的蛋白中的核酸酶)组合起作用。TAL核酸酶(TALN或TALEN)可以通过将TAL与核酸酶(例如N-末端或C-末端处的FokI核酸酶结构域)组合来构建,Kimet al.1996,PNAS 93:1156-1160;Christian et al 2010,Genetics 186:757-761;Li etal,2011;和Miller et al,2011。在大鼠、小鼠、斑马鱼、非洲爪蟾、青鳉、大鼠和人类细胞中,已证明了TALEN通过NHEJ导致缺失的功能(Ansai et al,2013;Carlson et al,2012;Hockemeyer et al,2011;Lei et al,2012;Moore et al,2012;Stroud et al,2013;Sunget al,2013;Wefers et al,2013)。
对于TALEN,其制备方法还记载于美国专利US8420782、US8450471、US8450107、US8440432、US8440431和美国专利申请US20130137161、US20130137174中。
其他有用的内切核酸酶可包括例如HhaI、HindIII、NotI、BbvCI、EcoRI、Bg/I和AlwI。可利用一些内切核酸酶(例如FokI)仅以二聚体发挥功能的事实来增强TAL效应物的靶向特异性。例如,在一些情况下,每个FokI单体均可与识别不同的DNA靶序列的TAL效应物序列融合,并且只有当这两个识别位点非常靠近时,所述非活性单体才会聚在一起以产生有功能的酶。通过需要DNA结合来激活核酸酶,可产生具有高度位点特异性的限制性酶。
在一些实施方案中,TALEN可进一步包括核定位信号或序列(NLS)。NLS是促进TALEN核酸酶蛋白靶向至细胞核内以在染色体中的靶序列处引入双链断裂的氨基酸序列。
核定位信号是本领域中已知的,参见例如Makkerh et al.1996,Curr Biol.6:1025-1027。NLS包括来自SV40大T抗原的序列PKKKRKV(SEQ ID NO:5),Kalderon 1984,Cell39:499-509;来自核质蛋白的RPAATKAGQAKKK(SEQ ID NO:6),Dingwall et al,1988,JCell Biol.107,841-9。其他实例记载在McLane and Corbett 2009,IUBMB Life 61,697-70;Dopie et al.2012,PNAS 109,E544-E552中。
裂解结构域可获自任何内切核酸酶或外切核酸酶。可从其中获得裂解结构域的内切核酸酶的非限制性实例包括但不限于,限制性内切核酸酶和归巢内切核酸酶。参见,例如,2002-2003Catalogue,New England Biolabs,Beverly,Mass.;和Belfort et al.(1997)Nucleic Acids Res.25:3379-3388。裂解DNA的其他酶是已知的,例如SI核酸酶、绿豆核酸酶、胰腺DNase I、微球菌核酸酶、酵母HO内切核酸酶。还参见Linn et al.(eds.)Nucleases,Cold Spring Harbor Laboratory Press,1993。这些酶或其功能片段中的一种或多种可用作裂解结构域的来源。
锌指介导的基因组编辑
锌指核酸酶(ZFN)用于基因编辑,特别是用于产生缺失的用途已经得到充分确立。例如参见Carbery et al,2010;Cui et al,2011;Hauschild et al,201 1;Orlando etal,2010;和Porteus&Carroll,2005。ZFN可通过引入非同源的末端连接(NHEJ)介导的缺失而用于产生敲除或通过同源性介导的修复过程而用于靶向插入。
锌指核酸酶介导的过程的组分包括具有DNA结合结构域和裂解结构域的锌指核酸酶。这些记载于例如Beerli et al.(2002)Nature Biotechnol.20:135-141;Pabo et al.(2001)Ann.Rev.Biochem.70:313-340;Isalan et al.(2001)Nature Biotechnol.19:656-660;Segal et al.(2001)Curr Opin.Biotechnol.12:632-637;和Choo et al.(2000)CurrOpin.Struct.Biol.10:41 1-416;以及美国专利No.6,453,242和6,534,261中。设计和选择针对靶序列的锌指结合结构域的方法是本领域中已知的,参见例如Biochemistry 2002,41,7074-7081;美国专利No.6,607,882、6,534,261和6,453,242中。在一些实施方案中,锌指核酸酶可进一步包含核定位信号或序列(NLS)。NLS是促进将锌指核酸酶蛋白靶向至细胞核以在染色体中的靶序列处引入双链断裂的氨基酸序列。核定位信号是本领域中已知的。参见,例如,Makkerh et al.(1996)Current Biology 6:1025-1027。裂解结构域可获自任何内切核酸酶或外切核酸酶。可从其中获得裂解结构域的内切核酸酶的非限制性实例包括但不限于限制性内切核酸酶和归巢内切核酸酶。参见,例如,2002-2003Catalog,NewEngland Biolabs,Beverly,Mass.;和Belfort et al.(1997)Nucleic Acids Res.25:3379-3388。裂解DNA的其他酶是已知的(例如,SI核酸酶、绿豆核酸酶、胰腺DNase I、微球菌核酸酶、酵母HO内切核酸酶)。还参见Linn et al.(eds.)Nucleases,Cold Spring HarborLaboratory Press,1993。这些酶(或其功能片段)中的一种或多种可用作裂解结构域的来源。如上所述,裂解结构域也可获自需要二聚化以产生裂解活性的酶或其部分。可能需要两个锌指核酸酶以进行裂解,因为每个核酸酶包括活性酶二聚体的一个单体。或者,单个锌指核酸酶可包括两个单体以产生活性酶二聚体。限制性内切核酸酶(限制性酶)存在于许多物种中,并且能够(在识别位点处)序列特异性结合DNA,并且在结合位点处或结合位点附近裂解DNA。某些限制性酶(例如IIS型)在远离识别位点的位点处裂解DNA,并具有可分离的结合结构域和裂解结构域。例如,IIS型酶FokI在一条链上距离其识别位点9个核苷酸处和在另一条链上距离其识别位点13个核苷酸处催化DNA的双链裂解。参见,例如,美国专利No.5,356,802;5,436,150和5,487,994;以及Li et al.(1992)PNAS 89:4275-4279;Li et al.(1993)PNAS 90:2764-2768;Kim et al.(1994)PNAS 91:883-887;Kim et al.(1994)J.Biol.Chem.269:31,978-31,982。因此,锌指核酸酶可包括来自至少一种IIS型限制性酶的裂解结构域和一个或多个锌指结合结构域(其可是经改造的或未经改造的)。示例性的IIS型限制性酶记载于例如国际公开WO 07/014275中,其公开内容以引用的方式全文纳入本文。其他限制酶还含有可分离的结合结构域和裂解结构域,并且本公开内容也考虑到这些。参见,例如Roberts et al.(2003)Nucleic Acids Res.31:418-420。示例性的IIS型限制性酶——其裂解结构域可与结合结构域分离——为FokI。这种特定的酶以二聚体形式时是有活性的(Bitinaite et al.1998,PNAS 95:10,570-10,575)。因此,出于本公开内容的目的,用于锌指核酸酶中的FokI酶的一部分被认为是裂解单体。因此,对于使用FokI裂解结构域的靶向双链裂解,可使用两个锌指核酸酶(各自包括一个FokI裂解单体)来重构活性酶二聚体。或者,也可使用含有锌指结合结构域和两个FokI裂解单体的单个多肽分子。在某些实施方案中,裂解结构域可包括一个或多个经改造的裂解单体,其最小化或防止同源二聚化,例如,如美国专利公开No.20050064474、20060188987和20080131962(其均以引用的方式全文纳入本文)中所记载的。作为非限制性实例,FokI的第446、447、479、483、484、486、487、490、491、496、498、499、500、531、534、537和538位处的氨基酸残基全部都是用于影响FokI裂解半结构域的二聚化的靶标。形成专性异源二聚体的FokI的示例性的经改造的裂解单体包括这样的对:其中第一裂解单体在FokI的第490和538位的氨基酸残基处包括突变、并且第二裂解单体在第486和499位的氨基酸残基处包括突变。因此,在一个实施方案中,第490位的氨基酸处的FokI突变用Lys(K)替换Glu(E);第538位的氨基酸残基处的突变用Lys(K)替换Ile(I);在第486位的氨基酸残基处的突变用Glu(E)替换Gin(Q);并且在第499位的突变用Lys(K)替换Ile(I)。具体地,FokI的经改造的裂解单体可如下制备:通过在一个裂解单体中将第490位从E突变为K和第538位从I突变为K来产生命名为“E490K:I538K”的经改造的裂解单体,以及通过在另一个裂解单体中将第486位从Q突变为E和第499位从I突变为L来产生命名为“Q486E:I499L”的经改造的裂解单体。上述经改造的裂解单体是其中异常裂解被最小化或消除的专性异源二聚体突变体。可使用适当的方法制备经改造的裂解单体,例如,通过如美国专利公开No.20050064474中记载的对野生型裂解单体(FokI)的定点诱变。
上述的锌指核酸酶可被改造以在整合的靶向位点处引入双链断裂。双链断裂可以在整合的靶向位点处,或者可远离整合位点最多达1、2、3、4、5、10、15、20、25、30、35、40、45、50、100或1000个核苷酸。在一些实施方案中,双链断裂可以远离整合位点最多达1、2、3、4、5、10、15或20个核苷酸。在其他实施方案中,双链断裂可以远离整合位点最多达10、15、20、25、30、35、40、45或50个核苷酸。在其他实施方案中,双链断裂可以远离整合位点最多达50、100或1000个核苷酸。
CRISPR-Cas系统
CRISPR(成簇的规律间隔的短回文重复序列)是包含多个短直接重复序列的基因座,其存在于约40%的已测序的细菌和90%的已测序的古细菌的基因组中并赋予对外源DNA元件的抗性,参见Horvath,2010,Science 327:167-170;Barrangou et al,2007;和Makarova et al,2011。CRISPR重复序列的大小范围为24至48个碱基对。它们通常显示一些二重对称性,意味着形成了诸如发夹的二级结构,但不是真正的回文结构。CRISPR重复序列是由具有相似长度的间隔序列分开。
CRISPR相关(cas)基因通常与CRISPR重复序列-间隔序列阵列相关联。已经记载了四十种以上的不同的Cas蛋白家族(Haft et al.2005,PLoS Comput Biol.1(6):e60)。Cas基因和重复序列结构的特定组合已被用于定义8种CRISPR亚型,其中一些与编码重复序列相关神秘蛋白(RAMP)的另外的基因模块相关。
在不同的生物体中有不同的CRISPR系统,其中最简单的一个是来自化脓链球菌(Streptococcus pyogenes)的II型CRISPR系统:仅编码Cas9蛋白的单个基因和两个RNA:成熟的CRISPR RNA(crRNA)和部分互补的反式作用RNA(tracrRNA),对于RNA引导的外源DNA沉默是必要和充分的(Gasiunas et al,2012;Jinek et al,2012)。crRNA的成熟需要tracrRNA和RNase III(Deltcheva et al,2011)。然而,这一要求可以通过使用改造的小导向RNA(sgRNA)来绕过,所述RNA含有模拟tracrRNA-crRNA复合物的设计的发夹(Jinek etal.,2012)。由于Cas9的内切核酸酶活性,sgRNA和靶DNA之间的碱基配对导致双链断裂(DSB)。通过sgRNA-DNA碱基配对以及与DNA互补区域并列的短DNA基序(原间隔序列临近基序[PAM]序列:NGG)来确定结合特异性(Marraffini&Sontheimer,2010)。例如,CRISPR系统需要两个分子的最小组——Cas9蛋白和sgRNA,因此可以用作宿主非依赖性基因靶向平台。最近,已经证明Cas9/CRISPR可被用于位点选择性RNA引导的基因组编辑(Carroll,2012;Chang et al,2013;Cho et al,2013;Cong et al,2013;Hwang et al,2013;Jiang et al,2013;Mali et al,2013;Qi et al,2013;Shen et al,2013;Wang et al,2013)。Wang etal,2013已证明当将CRISPR/Cas9系统与寡核苷酸组合时,使用CRISPR/Cas9系统进行靶向插入是可能的。
编码一种或多种核酸酶和/或一种或多种其他肽或蛋白(如TAL)的核酸可被克隆到表达载体中以用于转化至原核或真核细胞以及表达所编码的肽和/或蛋白。本文使用的“表达载体”被定义为当引入至合适的宿主细胞(例如,表达系统)中时可被转录并翻译成多肽的多聚核苷酸。体内“表达系统”是包含表达载体的合适宿主细胞,所述表达载体可起作用以产生所需的表达产物。表达载体也可用于在体外产生编码的蛋白,如在体外表达系统中。
表达载体可以是原核载体,例如质粒、或穿梭载体、昆虫载体或真核载体。
可使用本领域中已知的方法容易地设计核酸酶表达构建体。参见,例如,美国专利公开20030232410;20050208489;20050026157;20050064474;20060188987;20060063231;20080182332;2009011 188和国际公开WO 07/014,275。核酸酶的表达可以处于组成型启动子或诱导型启动子的控制之下。其他合适的细菌和真核生物启动子是本领域中公知的,并且记载于例如,Sambrook et al.,Molecular Cloning,A Laboratory Manual(第2版,1989;第3版,2001);Kriegler,Gene Transfer and Expression:A Laboratory Manual(1990);和Ausubel et al.,Current Protocols in Molecular Biology。用于表达蛋白的细菌表达系统可在例如大肠杆菌(E.coli)、芽孢杆菌属种(Bacillus sp.)、沙门氏菌(Salmonella)中获得,Palva et al.(1983)Gene 22:229-235。
除启动子之外,表达载体通常还含有转录单元或表达盒,其含有在宿主细胞(原核或真核)中表达核酸所需的所有额外元件,例如信号序列、增强子元件和转录终止序列。因此,典型的表达盒包含可操作地连接至例如编码核酸酶的核酸序列的启动子,以及例如转录物的有效多聚腺苷酸化、转录终止、核糖体结合位点或翻译终止所需的信号。所述盒的其他元件可包括例如增强子、异源剪接信号和/或核定位信号(NLS)。
合适的启动子和增强子元件是本领域中已知的。为了在细菌细胞中表达,合适的启动子包括但不限于lacI、lacZ、T3、T7、gpt、λP和trc。为了在真核细胞中表达,合适的启动子包括但不限于巨细胞病毒即刻早期启动子、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、存在于来自逆转录病毒的长末端重复序列中的启动子、小鼠金属硫蛋白-I启动子,和各种本领域已知的组织特异性启动子。
在一些实施方案中,例如为了在酵母细胞中表达,合适的启动子是组成型启动子,如ADH1启动子、PGK1启动子、ENO启动子、PYK1启动子等;或可调节的启动子,如GAL1启动子、GAL10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、HIS3启动子、ADH1启动子、PGK启动子、GAPDH启动子、ADC1启动子、TRP1启动子、URA3启动子、LEU2启动子、ENO启动子、TP1启动子和AOX1,例如用于毕赤酵母(Pichia)。合适的载体和启动子的选择完全在本领域普通技术人员的水平内。
用于原核宿主细胞的合适的启动子包括但不限于噬菌体T7RNA聚合酶启动子,trp启动子,lac操纵子启动子,杂合启动子如lac/tac杂合启动子、tac/trc杂合启动子、trp/lac启动子、T7/lac启动子,trc启动子,tac启动子等,araBAD启动子,体内调节型启动子如ssaG启动子或相关启动子,参见例如美国专利公开No.20040131637;pagC启动子,参见Pulkkinen and Miller,J.Bacteriol,1991:173(1):86-93;Alpuche-Aranda et al.,PNAS,1992;89(21):10079-83;nirB启动子,参见Harborne et al.(1992)Mol.Micro.6:2805-2813;等等,参见例如Dunstan et al.(1999)Infect.Immun.67:5133-5141;McKelvieet al.(2004)Vaccine 22:3243-3255;和Chatfield et al.(1992)Biotechnol.10:888-892);σ70启动子,例如共有σ70启动子(参见GenBank登录号AX798980、AX798961和AX798183),固定相启动子如dps启动子、spv启动子等;来自致病岛SPI-2的启动子,参见例如WO96/17951;actA启动子,参见例如Shetron-Rama et al.(2002)Infect.Immun.70:1087-1096;rps M启动子,参见例如Valdivia and Falkow(1996).Mol.Microbiol.22:367;Tet(四环素)启动子,参见例如Hillen,W.and Wissmann,A.(1989)in Saenger,W.andHeinemann,U.(eds),Topics in Molecular and Structural Biology,Protein-NucleicAcid Interaction.Macmillan,London,UK,第10卷,第143-162页;SP6启动子,参见例如Melton et al.(1984)Nucl.Acids Res.12:7035;等等。用于原核生物(如大肠杆菌)的合适的强启动子包括但不限于Trc、Tac、T5,T7和pλ。用于细菌宿主细胞的操纵子的非限制性实例包括乳糖启动子操纵子(当与乳糖接触时Lac1阻遏蛋白改变构象,由此防止Lac1阻抑蛋白与操纵子结合),色氨酸启动子操纵子(当与色氨酸复合时,TrpR阻遏蛋白具有结合操纵子的构象;在不存在色氨酸的情况下,TrpR阻遏蛋白具有不与操纵子结合的构象)和tac启动子操纵子,参见例如deBoer etal.(1983)PNAS 80:21-25。
用于这种表达系统的试剂盒是市售可得的。用于哺乳动物细胞的真核表达系统是本领域技术人员公知的并且也是市售可得的。
可使用任何用于将外源核苷酸序列引入至宿主细胞的公知方法。这些包括使用磷酸钙转染、聚凝胺、原生质体融合、电穿孔、超声法(例如,声致穿孔)、脂质体、显微注射、裸DNA、质粒载体、病毒载体(游离型和整合型),以及任何其他的用于将克隆的基因组DNA、cDNA、合成的DNA或其他外源遗传物质引入至宿主细胞的公知方法(参见例如Sambrook etal.,见上文)。仅需要所使用的特定遗传工程方法能够成功地将至少一个基因导入至能够表达所选蛋白的宿主细胞中。
例如,如Jinek et al.,2012中所记载的,从载体pMJ806和pMJ841克隆Cas9和dCas9基因。对所述基因进行PCR扩增并插入到含有Tc-诱导型启动子PLtetO-1(Lutz andBujard,1997,Nucleic Acids Res.25:1203-10)、氯霉素选择标记和p15A复制起点的载体中。将sgRNA模板克隆到含有最小合成启动子(J23119)(具有注释的转录起始位点)、氨苄青霉素选择标记和ColE1复制起点的载体中。使用反向PCR产生具有新的20bp互补区的sgRNA盒。表达系统记载于例如Cong et al,2013;和Jinek et al,2012中。
根据本发明的方面,将供体寡核苷酸与包括TAL、ZFN、CRJSPR和DRAP的基因编辑系统组合使用。
用于编辑Rhbdf2基因的染色体序列以产生突变的方法包括引入至少一个供体寡核苷酸,所述供体寡核苷酸包括将Rhbdf2基因的突变引入至受精的卵母细胞、胚胎或细胞中的序列。供体寡核苷酸包括至少三种组分:编码Rhbdf2突变序列的序列、上游序列和下游序列。编码所述蛋白的序列的侧翼为上游和下游序列,其中上游和下游序列与染色体中整合位点的任一侧具有序列相似性。
通常,供体寡核苷酸将是DNA。供体寡核苷酸可以是DNA质粒、线性DNA片段、PCR片段、裸核酸、单链核酸、合成的寡核苷酸或与递送载体(如脂质体或泊洛沙姆)复合的核酸。在一个优选的实施方案中,所述供体寡核苷酸是单链的。
本发明提供了用于突变小鼠Rhbdf2基因的特定寡核苷酸。
用于在野生型Rhbdf2基因序列(SEQ ID NO:2)中引入点突变p.P159L的供体寡核苷酸是:
SEQ ID NO:4的供体寡核苷酸的变体可用于在野生型Rhbdf2基因序列中引入点突变p.P159L。例如,使用供体寡核苷酸变体在野生型Rhbdf2基因序列中引入点突变p.P159L以产生具有P159L和N-末端突变的突变iRhom2。
根据本发明的方面,供体寡核苷酸与SEQ ID NO:4具有至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%的同一性或更高的同一性,其中所述变体编码与由SEQ ID NO:4编码的氨基酸序列相同的氨基酸序列。
还发现用于引入点突变p.P159L的供体寡核苷酸(SEQ ID NO:4)可有效用于引入点突变p.I156T和p.D158N。此外,还发现SEQ ID NO:4的供体寡核苷酸可有效用于将多个点突变(特别是p.P159L、p.I156T和p.D158N中的两个或更多个的组合,或所有这三个突变)引入到免疫缺陷小鼠的基因组中。
供体核苷酸变体包括与本文公开的那些不同、但由于遗传密码的简并性而编码野生型或突变的iRhom2的所需部分的那些。
当比较参照蛋白与推定的同源物时,除了氨基酸序列中的相应位置处的氨基酸的同一性之外,还可考虑氨基酸相似性。“氨基酸相似性”是指与参照蛋白中相应的氨基酸位置相比,推定的同源物中的氨基酸同一性和保守性氨基酸置换。
可在参照蛋白中进行保守性氨基酸置换以产生变体。
保守性氨基酸置换是本领域公认的一个氨基酸与具有相似特征的另一个氨基酸的置换。例如,每个氨基酸可被描述为具有一个或多个以下特征:正电性、负电性、脂肪族、芳香族、极性、疏水性和亲水性。保守性置换是具有特定结构或功能特征的一个氨基酸置换具有相同特征的另一个氨基酸。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;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、甲硫氨酸、脯氨酸、缬氨酸和色氨酸;并且保守性置换包括在每组内的氨基酸之间的置换。氨基酸也可用相对大小来描述,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——所有这些通常都被认为很小。
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,示例性地包括但不限于α-氨基丁酸、瓜氨酸、刀豆氨酸、氰基丙氨酸、二氨基丁酸、二氨基庚二酸、二羟基-苯丙氨酸、S-亚甲胱氨酸、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。
关于核酸,本领域技术人员将会理解,由于遗传密码的简并性质,多个核酸序列可编码特定的蛋白,并且这样的替代核酸可用于本发明的组合物和方法中。
通过比较氨基酸或核酸序列(包括参照氨基酸或核酸序列和推定的同源氨基酸或核酸序列)来确定同一性百分数。为确定两条氨基酸序列或两条核酸序列的同一性百分数,出于最佳比较目的将序列进行比对(例如,可将空位引入到第一氨基酸或核酸序列的序列中以与第二氨基酸或核酸序列进行最佳比对)。然后比较相应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置与第二序列中的相应位置被相同的氨基酸残基或核苷酸占据时,则所述分子在该位置处是相同的。两条序列之间的同一性百分数是所述序列共有的相同位置的数目的函数(即,%同一性=相同的重叠位置的数目/位置的总数X 100%)。所比较的两条序列通常具有相同的长度或几乎相同的长度。
两条序列之间的同一性百分数的确定也可使用数学算法来完成。用于确定同一性百分数的算法示例性地包括S.Karlin and S.Altshul,PNAS,90:5873-5877,1993;T.Smithand M.Waterman,Adv.Appl.Math.2:482-489,1981,S.Needleman and C.Wunsch,J.Mol.Biol.,48:443-453,1970,W.Pearson and D.Lipman,PNAS,85:2444-2448,1988的算法,和纳入计算机化执行的其他算法,例如但不限于,例如纳入在Wisconsin GeneticsSoftware Package,Genetics Computer Group,575Science Drive,Madison,Wis.中并且可从国家生物技术信息中心(National Center for Biotechnology Information)公开获得的GAP、BESTFIT、FASTA、TFASTA和BLAST。
用于比较两条序列的数学算法的非限制性实例是Karlin and Altschul,1990,PNAS 87:2264-2268的算法,其在Karlin and Altschul,1993,PNAS.90:5873-5877中被改进。这种算法被纳入到Altschul et al.,1990,J.Mol.Biol.215:403中的NBLAST和XBLAST程序中。使用NBLAST核苷酸程序参数设置(例如评分=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。使用XBLAST程序参数设置(例如评分=50,字长=3)进行BLAST蛋白质搜索以获得与本发明的蛋白质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,如Altschul et al.,1997,Nucleic Acids Res.25:3389-3402中所述使用Gapped BLAST。或者,使用PSI BLAST来进行检测分子间远缘关系的迭代搜索。当使用BLAST、Gapped BLAST和PSI Blast程序时,使用各个程序(例如,XB LAST和NBLAST)的默认参数。用于比较序列的数学算法的另一个优选的非限制性实例是Myers andMiller,1988,CABIOS 4:1 1-17的算法。这种算法被纳入ALIGN程序(版本2.0)中,该程序是GCG序列比对软件包的一部分。当使用ALIGN程序比较氨基酸序列时,使用PAM120权重残基表,空位长度罚分为12,空位罚分为4。
使用类似于上述的技术在允许或不允许空位的情况下确定两条序列之间的同一性百分数。在计算同一性百分数时,通常只计算精确匹配。
本领域技术人员将认识到,可分别引入一个或多个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。
可通过将基因靶向载体导入到植入前胚胎或干细胞(如胚胎干(ES)细胞或诱导多能干(iPS)细胞)来实现产生其基因组包括Rhbdf2基因突变的经遗传修饰的免疫缺陷小鼠。
术语“基因靶向载体”是指例如通过插入至靶基因中或替换靶基因而有效与特定染色体基因座重组并使其突变的双链重组DNA分子。
对于靶向基因突变,基因靶向载体是使用重组DNA技术来制备并且包括与干细胞内源Rhbdf2基因同源的5'和3'序列。基因靶向载体任选且优选地进一步包括选择标记,如新霉素磷酸转移酶、潮霉素或嘌呤霉素。本领域普通技术人员仅通过常规实验就能够选择用于包括在基因靶向载体中的序列,并且使用这些序列。可使用公知的方法通过重组或合成来产生基因靶向载体。
对于基因靶向载体向植入前胚胎中的DNA注射的方法,在注射到非人类植入前胚胎中之前将基因靶向载体线性化。优选地,将基因靶向载体注射到受精的卵母细胞中。交配后的第二天(0.5dpc)从超排卵雌性中收集受精的卵母细胞并用表达构建体进行注射。将经注射的卵母细胞培养过夜或直接转移到0.5天p.c.的假孕雌性的输卵管中。用于超排卵、收集卵母细胞、基因靶向载体注射和胚胎转移的方法是本领域中已知的,并记载于Manipulating the Mouse Embryo:A Laboratory Manual,第3版,Cold Spring HarborLaboratory Press;December 15,2002,ISBN-10:0879695919中。可以通过DNA分析(如PCR、DNA印迹或测序)测试后代中Rhbdf2基因突变的存在。例如通过使用ELISA或蛋白质印迹分析和/或mRNA表达如通过RT-PCR,可测试具有Rhbdf2基因突变的小鼠中的iRhom蛋白表达。
或者,可使用公知的方法(如电穿孔、磷酸钙沉淀和脂质转染)将基因靶向载体转染到干细胞(ES细胞或iPS细胞)中。
使小鼠ES细胞在针对特定品系进行优化的培养基中生长。通常,ES培养基包含溶于Dulbecco's Modified Eagle Media(DMEM)中的15%胎牛血清(FBS)或合成或半合成等价物、2mM谷氨酰胺、1mM丙酮酸钠、0.1mM非必需氨基酸、50U/mL青霉素和链霉素、0.1mM2-巯基乙醇和1000U/mL LIF(对于某些细胞系,加上化学分化抑制剂)。详细描述是本领域中已知的(Tremml et al.,2008,Current Protocols in Stem Cell Biology,Chapter l:Unit1C.4)。关于ES细胞分化抑制剂的综述,参见Buehr,M.,et al.,2003.Genesis ofembryonic stem cells.Philosophical Transactions of the Royal Society B:Biological Sciences 358,1397-1402。
通过DNA分析(例如PCR、DNA印迹或测序)筛选细胞中的Rhbdf2基因突变。例如通过使用ELISA或蛋白质印迹分析和/或mRNA表达如通过RT-PCR,可测试具有导致Rhbdf2基因突变的正确同源重组事件的细胞中的iRhom蛋白表达。如果需要,可以通过用Cre重组酶处理干细胞来去除选择标记。在Cre重组酶处理后,分析细胞中编码突变的iRhom2的核酸的存在。
可将具有使Rhbdf2基因突变的正确的基因组事件的所选干细胞注射到植入前胚胎中。对于显微注射,使用胰蛋白酶和EDTA的混合物将ES或iPS细胞提供给单细胞,随后在ES培养基中重悬。使用精细抽取的玻璃针(内径20-25微米)选择单细胞群,并使用装有显微操作器的倒置显微镜将其穿过胚胎的透明带引入到囊胚腔中。作为囊胚注射的替代方案,可将干细胞注射到早期胚胎(例如2-细胞、4-细胞、8-细胞、前桑椹胚或桑椹胚)中。注射可用钻开透明带的激光或压电脉冲来辅助。每个囊胚或8-细胞期胚胎注射约9-10个所选的干细胞(ES或iPS细胞),每个4-细胞期胚胎注射6-9个干细胞,并且每个2-细胞期胚胎注射约6个干细胞。在引入干细胞之后,允许胚胎在含5%CO2、5%O2的氮气中在37℃下恢复数小时,或者培养过夜,然后转移至假孕的受体雌性中。在干细胞注射的其他替代方案中,可将干细胞与桑椹胚期胚胎聚集。所有这些方法都已充分确立并可用于产生干细胞嵌合体。对于更详细的描述,参见Manipulating the Mouse Embryo:A Laboratory Manual,第3版,Nagyet al.,Cold Spring Harbor Laboratory Press;December 15,2002,ISBN-10:0879695919,1990,Development 110,815-821;US 7,576,259;US 7,659,442;US 7,294,754;和Kraus et al,2010,Genesis 48,394-399。
使用本领域已知的方法来制备假孕胚胎受体。简言之,将6-8周龄的能育雌性小鼠与切除输精管的或不育的雄性交配,以诱导有助于支持通过手术引入的胚胎的激素状态。在交配后2.5天(dpc),将最多达15个含有囊胚的干细胞引入到非常接近子宫-输卵管连接处的子宫角。对于早期胚胎和桑椹胚,将这些胚胎体外培养成囊胚或根据胚胎阶段将其植入到0.5dpc或1.5dpc的假孕雌性的输卵管中。根据植入时的胚胎年龄,转移后16-20天,来自所植入的胚胎的嵌合幼仔出生。选择嵌合雄性用于繁殖。可通过毛发减少的外观(即无毛表型)和/或核酸分析(例如PCR、DNA印迹或测序)来分析后代中ES细胞基因组的传递。此外,突变的iRhom的表达可通过检测编码突变iRhom的mRNA或突变蛋白表达(如通过蛋白分析,例如免疫测定或功能测定)来测定,以确认Rhbdf2基因突变。使具有Rhbdf2基因突变的后代互交以产生Rhbdf2基因突变纯合型的非人类动物。将转基因小鼠与免疫缺陷小鼠杂交以产生具有Rhbdf2基因突变的同类系(congenic)免疫缺陷品系。
评估经遗传修饰的非人类动物以确定Rhbdf2基因是否被突变以使得小鼠表达突变的Rhbdf2基因的方法是公知的,并且包括标准技术如核酸测定、光谱测定、免疫测定和功能测定。
一个或多个标准可用于允许对样品中的iRhom进行定量测定。
可进行用于评估具有推定的突变Rhbdf2基因的小鼠中的突变iRhom2的功能的测定。用于评估具有推定的Rhbdf2基因突变的小鼠中推定的突变iRhom2的功能的测定包括评估小鼠的毛发。
任选地,通过选择性繁殖产生本发明的经遗传修饰的免疫缺陷小鼠。可将具有第一所需基因型的小鼠的第一亲代品系与具有第二所需基因型的小鼠的第二亲代品系交配以产生后代,所述后代是具有所述第一和第二所需基因型的经遗传修饰的小鼠。例如,可将具有免疫缺陷的第一小鼠与具有Rhbdf2基因突变的第二小鼠交配,以产生具有免疫缺陷、Rhbdf2基因突变并表达由Rhbdf2基因突变编码的突变iRhom2的后代,导致与没有所述一个或多个Rhbdf2基因突变的相同背景的小鼠相比,所述包括一个或多个Rhbdf2基因突变的经遗传修饰的免疫缺陷小鼠具有无毛表型和异种肿瘤生长的增加。
在其他实例中,可将NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG)小鼠、NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac(NOG)小鼠或NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ(NRG)小鼠与具有Rhbdf2基因突变的小鼠交配以产生具有免疫缺陷、Rhbdf2基因突变并表达由Rhbdf2基因突变编码的突变iRhom2的后代,导致携带所述突变的免疫缺陷后代的无毛表型和异种肿瘤生长的增加。
本发明的方面提供了在基本上所有细胞中包括Rhbdf2基因突变的经遗传修饰的免疫缺陷小鼠,以及在一些但不是所有细胞中包括Rhbdf2基因突变的经遗传修饰的免疫缺陷小鼠。
根据本发明的方面,将异种肿瘤细胞给予至本发明的经遗传修饰的免疫缺陷小鼠,所述小鼠具有突变的Rhbdf2基因,以使得小鼠表达相应的突变iRhom,导致无毛表型以及来自给予至所述小鼠的异种肿瘤细胞的异种肿瘤生长的增加,提供了增殖性疾病的肿瘤模型。根据本发明的方面,将异种肿瘤细胞给予至本发明的经遗传修饰的NSG、NOG或NRG小鼠,所述小鼠具有突变的Rhbdf2基因,以使得小鼠表达相应的突变iRhom2,导致无毛表型以及来自给予至小鼠的异种肿瘤细胞的异种肿瘤生长的增加。
根据本发明的方面,将异种肿瘤细胞给予至NOD.Cg-PrkdcscidIl2rgtm1Wjl RhbdfI156X/SzJ小鼠、NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf D158X/SzJ小鼠或NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf P159X/SzJ小鼠,其中与没有Rhbdf2基因突变的相同背景的小鼠相比,所述小鼠具有无毛表型和异种肿瘤生长的增加。
根据本发明的方面,将异种肿瘤细胞给予至NOD.Cg-PrkdcscidIl2rgtm1Wjl RhbdfI156T/SzJ小鼠、NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf D158N/SzJ小鼠或NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf P159L/SzJ小鼠,其中与没有Rhbdf2基因突变的相同背景的小鼠相比,所述小鼠具有无毛表型和异种肿瘤生长的增加。
给予至本发明的经遗传修饰的免疫缺陷小鼠的异种肿瘤细胞可以是多种肿瘤细胞中的任一种,包括但不限于肿瘤细胞系的细胞和原发性肿瘤细胞。异种肿瘤细胞可来自多种生物体中的任一种,优选哺乳动物,包括人、非人灵长类动物、大鼠、豚鼠、兔、猫、狗、马、牛、山羊、猪和绵羊。
根据本发明的具体方面,异种肿瘤细胞是人肿瘤细胞。根据本发明的具体方面,人肿瘤细胞存在于获自人的样品中,例如但不限于血液样品、组织样品或通过人类肿瘤的活组织检查获得的样品。
获自人的肿瘤细胞可被直接给予至本发明的经遗传修饰的免疫缺陷小鼠,或者可在给予至小鼠之前在体外培养。
本文使用的术语“肿瘤”是指以不受调控的生长为特征的细胞,包括但不限于肿瘤前期过度增殖、原位癌、肿瘤、转移瘤以及实体瘤和非实体瘤。肿瘤的实例是由癌症引起的那些,包括但不限于淋巴瘤、白血病、鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状癌、腹膜癌、肾上腺癌、肛门癌、胆管癌、膀胱癌、脑癌、乳腺癌、三阴性乳腺癌、中枢或周围神经系统癌症、宫颈癌、结肠癌、结肠直肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠癌、成胶质细胞瘤、头颈癌、肾癌、肝癌、鼻咽癌、鼻腔癌、口咽癌、口腔癌、骨肉瘤、卵巢癌、胰腺癌、甲状旁腺癌、垂体癌、前列腺癌、视网膜母细胞瘤、肉瘤、唾液腺癌、皮肤癌、小肠癌、胃癌、睾丸癌、胸腺癌、甲状腺癌、子宫癌、阴道癌和外阴癌。
肿瘤细胞可通过多种途径给予,例如但不限于皮下注射、腹膜内注射或注射到尾静脉。
异种肿瘤细胞的植入可通过多种方法中的任一种来评估,例如但不限于目测检查小鼠的肿瘤形成征象。
所给予的肿瘤细胞的数目被视为非限制性的。单个肿瘤细胞可以在本文所述的经遗传修饰的免疫缺陷动物中扩增为可检测的肿瘤。所给予的肿瘤细胞的数目通常在1000-1X 106个肿瘤细胞的范围内,尽管可给予更多或更少的肿瘤细胞。
与没有Rhbdf2基因突变的相同背景的免疫缺陷小鼠相比,可在具有本发明的Rhbdf2基因突变的经遗传修饰的免疫缺陷小鼠(其中所述免疫缺陷小鼠表达在N-末端区域具有突变的相应iRhom2)中观察到异种肿瘤生长的增加。所述增加可以是任何可检测的增加,例如,在相同时间段内与没有Rhbdf2基因突变的相同背景的免疫缺陷小鼠相比,肿瘤体积的1%或更多的增加;例如,在相同时间段内与没有Rhbdf2基因突变的相同背景的免疫缺陷小鼠相比,肿瘤体积的20%、30%、40%、50%、60%、70%、80%、90%、100%、200%、300%、400%、500%、600%、700%、800%、900%、1000%或更多的增加。
可使用多种方法中的任一种来测量异种肿瘤的生长,包括但不限于在活小鼠中的测量、对从活小鼠中切除的肿瘤的测量或对原位肿瘤或对从死小鼠中切除的肿瘤的测量。可使用测量仪器(如卡尺)来获得测量值,使用一种或多种成像技术(如超声波检查、计算机断层扫描、正电子发射断层摄影、荧光成像、生物发光成像、磁共振成像以及这些中的任意两种或更多种的组合)或者其他肿瘤测量方法进行测量。从携带异种肿瘤细胞的小鼠获得的样品中的肿瘤细胞数目可用于测量肿瘤生长,特别是对于非实体瘤。例如,可以评估血液样品中非实体瘤细胞的数目以获得对小鼠中非实体瘤生长的测量。
根据本发明方面的用于鉴定组合物的抗肿瘤活性的方法包括提供具有突变的Rhbdf2基因的经遗传修饰的免疫缺陷小鼠,以使得所述经遗传修饰的免疫缺陷小鼠表达相应的突变iRhom,并且与没有Rhbdf2基因突变的相同背景的小鼠相比具有无毛表型和异种肿瘤生长的增加;将异种肿瘤细胞给予至所述经遗传修饰的免疫缺陷小鼠,其中所述异种肿瘤细胞在经遗传修饰的免疫缺陷小鼠中形成实体瘤或非实体瘤;将测试化合物给予至所述经遗传修饰的免疫缺陷小鼠;测定所述异种肿瘤和/或肿瘤细胞对所述测试化合物的反应,其中所述测试物质对肿瘤和/或肿瘤细胞的抑制作用将所述测试物质鉴定为具有抗肿瘤活性。
根据本发明方面的用于鉴定组合物的抗肿瘤活性的方法包括提供包含突变的Rhbdf2基因的经遗传修饰的NSG、NOG或NRG小鼠,以使得所述经遗传修饰的免疫缺陷小鼠表达相应的突变iRhom,并且与没有Rhbdf2基因突变的相同背景的小鼠相比具有无毛表型和异种肿瘤生长的增加;将异种肿瘤细胞给予至所述经遗传修饰的免疫缺陷小鼠,其中所述异种肿瘤细胞在经遗传修饰的免疫缺陷小鼠中形成肿瘤;将测试化合物给予至所述经遗传修饰的免疫缺陷小鼠;测定所述异种肿瘤和/或肿瘤细胞对所述测试化合物的反应,其中所述测试物质对肿瘤和/或肿瘤细胞的抑制作用将所述测试物质鉴定为具有抗肿瘤活性。
根据本发明方面的用于鉴定组合物的抗肿瘤活性的方法包括提供包含Rhbdf2基因突变的经遗传修饰的NSG小鼠,以使得所述经遗传修饰的NSG小鼠表达在N-末端区域具有突变的相应的突变iRhom,其中与没有Rhbdf2基因突变的相同背景的小鼠相比,所述小鼠具有无毛表型和异种肿瘤生长的增加;将异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,其中所述异种肿瘤细胞在经遗传修饰的NSG小鼠中形成肿瘤;将测试化合物给予至所述经遗传修饰的NSG小鼠;测定所述异种肿瘤和/或肿瘤细胞对所述测试化合物的反应,其中所述测试物质对肿瘤和/或肿瘤细胞的抑制作用将所述测试物质鉴定为具有抗肿瘤活性。
用于鉴定根据本发明方面的组合物的抗肿瘤活性的方法包括提供NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf I156X/SzJ小鼠、NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf D158X/SzJ小鼠或NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf P159X/SzJ小鼠,所述小鼠与没有Rhbdf2基因突变的相同背景的小鼠相比具有无毛表型和异种肿瘤生长的增加;将异种肿瘤细胞给予至所述小鼠,其中所述异种肿瘤细胞在所述小鼠中形成肿瘤;将测试化合物给予至所述小鼠;测定所述异种肿瘤和/或肿瘤细胞对所述测试化合物的反应,其中所述测试物质对肿瘤和/或肿瘤细胞的抑制作用将所述测试物质鉴定为抗肿瘤组合物。
根据本发明方面的用于鉴定组合物的抗肿瘤活性的方法包括提供NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf I156T/SzJ小鼠、NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf D158N/SzJ小鼠或NOD.Cg-PrkdcscidIl2rgtm1Wjl Rhbdf P159L/SzJ小鼠,所述小鼠与没有Rhbdf2基因突变的相同背景的小鼠相比具有无毛表型和异种肿瘤生长的增加;将异种肿瘤细胞给予至所述小鼠,其中所述异种肿瘤细胞在所述小鼠中形成肿瘤;将测试化合物给予至所述小鼠;测定所述异种肿瘤和/或肿瘤细胞对所述测试化合物的反应,其中所述测试物质对肿瘤和/或肿瘤细胞的抑制作用将所述测试物质鉴定为具有抗肿瘤活性。
根据本发明方法的方面,测定异种肿瘤和/或肿瘤细胞对测试化合物的反应包括将所述反应与标准进行比较以确定测试物质对异种肿瘤细胞的作用,其中所述测试物质对异种肿瘤细胞的抑制作用将测试物质鉴定为抗肿瘤组合物。标准是本领域中公知的,并且所使用的标准可以是任何适当的标准。在一个实例中,标准是已知具有抗肿瘤作用的化合物。在其他实例中,对可比较的异种肿瘤的不处理提供了不经处理的肿瘤生长的基线水平指示,以用于比较测试物质的作用。标准可以是预期肿瘤生长的参照水平,其之前在可比较的小鼠个体中或在可比较的小鼠群体中测定,并被存储在打印介质或电子介质中以用于调用并与测定结果进行比较。
可通过多种方法中的任一种使用统计学分析来分析测定结果,以确定所述测试物质是否对肿瘤具有抑制作用,例如通过参数或非参数检验、方差分析、协方差分析、多变量逻辑回归分析、Fisher精确检验、卡方检验、Student's T检验、Mann-Whitney检验、Wilcoxon符号秩检验、McNemar检验、Friedman检验和Page's L趋势检验。这些和其他统计学检验是本领域中公知的,如Hicks,CM,Research Methods for Clinical Therapists:Applied Project Design and Analysis,Churchill Livingstone(publisher);第5版,2009;和Freund,RJ et al.,Statistical Methods,Academic Press;第3版,2010。
本文使用的术语“抑制作用”是指测试物质抑制肿瘤生长、肿瘤细胞代谢和肿瘤细胞分裂中的一种或多种的作用。
用于本发明方法中的测试物质可以是任何化学实体,示例性地包括合成或天然存在的化合物或者合成或天然存在的化合物的组合、小的有机或无机分子、蛋白质、肽、核酸、碳水化合物、寡糖、脂质或任何这些的组合。
根据本发明的方面,测试物质是抗癌剂。
抗癌剂记载于例如Brunton et al.(eds.),Goodman and Gilman's ThePharmacological Basis of Therapeutics,第12版,Macmillan Publishing Co.,2011中。
抗癌剂示例性地包括阿西维辛(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)、别嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、安波霉素(ambomycin)、阿美蒽醌(ametantrone)、阿米福汀(amifostine)、氨鲁米特(aminoglutethimide)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、安曲霉素(anthramycin)、三氧化二砷(arsenic trioxide)、天冬酰胺酶(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)、苄替哌(benzodepa)、比卡鲁胺(bicalutamide)、比生群(bisantrene)、双奈法德(bisnafide dimesylate)、比折来新(bizelesin)、博来霉素(bleomycin)、布喹那(brequinar)、溴匹立明(bropirimine)、白消安(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)、cedefmgol、塞来昔布(celecoxib)、苯丁酸氮芥(chlorambucil)、西罗霉素(cirolemycin)、顺铂(cisplatin)、克拉屈滨(cladribine)、考比替尼(cobimetinib)、甲磺酸克里斯奈托(crisnatol mesylate)、环磷酰胺(cyclophosphamide)、阿糖孢苷(cytarabine)、达卡巴嗪(dacarbazine)、放线菌素(dactinomycin)、道诺霉素(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)、亚丝醌(diaziquone)、多西他赛(docetaxel)、阿霉素(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)、雌莫司汀(estramustine)、依他硝唑(etanidazole)、依托泊苷(etoposide)、艾托卜宁(etoprine)、法倔唑(fadrozole)、法扎拉滨(fazarabine)、芬维A胺(fenretinide)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟二氧嘧啶(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(IL-2,包括重组的白细胞介素II或rIL2)、干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素α-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)、环己亚硝脲(lomustine)、洛索蒽醌(losoxantrone)、马索罗酚(masoprocol)、美登素(maytansine)、盐酸氮芥(mechlorethamine hydrochlride)、甲地孕酮(megestrol)、醋酸美仑孕酮(melengestrolacetate)、美法仑(melphalan)、美诺立尔(menogaril)、巯嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、氯苯氨啶(metoprine)、美妥替哌(meturedepa)、米丁度胺(mitindomide)、mitocarcin、mitocromin、米托洁林(mitogillin)、米托马星(mitomalcin)、丝裂霉素(mitomycin)、丝裂帕菌素(mitosper)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、霉酚酸(mycophenolic acid)、奈拉滨(nelarabine)、诺考达唑(nocodazole)、诺加霉素(nogalamycin)、ormnaplatin、奥昔舒仑(oxisuran)、紫杉醇(paclitaxel)、培门冬酶(pegaspargase)、培利霉(peliomycin)、戊氮芥(pentamustine)、培洛霉素(peplomycin)、培磷酰胺(perfosfamide)、哌泊溴烷(pipobroman)、嗪消安(piposulfan)、罗蒽醌(piroxantrone hydrochloride)、普卡霉素(plicamycin)、普洛美坦(plomestane)、卟菲尔钠(porfimer)、甲基丝裂霉素(porfiromycin)、泼尼氮芥(prednimustine)、甲基苄肼(procarbazine)、嘌呤霉素(puromycin)、吡唑呋喃菌素(pyrazofurin)、异戊烯腺苷(riboprine)、罗谷亚胺(rogletimide)、沙芬戈(safingol)、甲基环己亚硝脲(semustine)、辛曲秦(simtrazene)、sparfosate、司帕霉素(sparsomycin)、锗螺胺(spiro germanium)、螺莫司汀(spiromustine)、螺铂(spiroplatin)、链黑菌素(streptonigrin)、链脲菌素(streptozocin)、磺氯苯脲(sulofenur)、他利霉素(talisomycin)、三苯氧胺(tamoxifen)、替可加兰(tecogalan)、喃氟啶(tegafur)、替洛蒽醌(teloxantrone)、temoporfm、替尼泊苷(teniposide)、替罗昔隆(teroxirone)、睾内酯(testolactone)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine)、噻替派(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)、曲美沙特(trimetrexate)、曲普瑞林(triptorelin)、九布洛唑(tubulozole)、乌拉莫司汀(uracil mustard)、乌瑞替哌(uredepa)、伐普肽(vapreotide)、维莫非尼(vemurafenib)、verteporfm、长春花碱(vinblastine)、硫酸醛基长春碱(vincristine sulfate)、长春地辛(vindesine)、长春匹定(vinepidine)、长春甘酯(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)、新制癌菌素(zinostatin)、唑来膦酸(zoledronate)和佐柔比星(zorubicin)。
根据本发明的方面,抗癌剂是抗癌抗体。所使用的抗癌抗体可以是有效抑制至少一种类型的肿瘤,特别是人类肿瘤的任何抗体。抗癌抗体包括但不限于3F8、8H9、阿巴伏单抗(abagovomab)、abituzumab、阿达木单抗(adalimumab)、阿德木单抗(adecatumumab)、阿杜卡尼单抗(aducanumab)、阿夫土珠单抗(afutuzumab)、培化阿珠单抗(alacizumabpegol)、阿仑单抗(alemtuzumab)、阿麦妥昔(amatuximab)、麻安莫单抗(anatomicomamafenatox)、anetumab ravtansine、阿泊珠单抗(apolizumab)、阿西莫单抗(arcitumomab)、ascrinvacumab、atezolizumab、巴维昔单抗(bavituximab)、贝利木单抗、贝伐单抗、莫-比伐珠单抗(bivatuzumab mertansine)、贝伦妥单抗-维多汀(brentuximabvedotin)、brontictuzumab、莫-坎妥珠单抗(cantuzumab mertansine)、拉-坎妥珠单抗(cantuzumab ravtansine)、卡罗单抗-喷地肽(capromab pendetide)、卡妥索单抗、西妥昔单抗、泊-西他珠单抗(citatuzumab bogatox)、西妥木单抗(cixutumumab)、克莱维足单抗(clivatuzumab tetraxetan)、可那木单抗(conatumumab)、达西珠单抗(dacetuzumab)、达洛珠单抗(dalotuzumab)、登西珠单抗(demcizumab)、denintuzumab mafodotin、depatuxizumabmafodotin、度伐单抗(durvalumab)、杜氏图单抗(dusigitumab)、依决洛单抗(edrecolomab)、依洛珠单抗(elotuzumab)、emavatuzumab、emibetuzumab、enoblituzumab,enfortumab vedotin,埃文单抗(enavatuzumab),依帕珠单抗(epratuzumab),厄马索单抗(ertumaxomab),埃达珠单抗(etaracizumab)、法勒珠单抗(farletuzumab)、费希腊妥单抗(ficlatuzumab)、芬妥木单抗(figitumumab)、弗兰托单抗(flanvotumab)、弗图希单抗(futuximab)、加利昔单抗(galiximab)、盖尼塔单抗(ganitumab)、吉妥珠单抗(gemtuzumab)、吉瑞昔单抗(girentuximab)、格莱木单抗-维多汀(glembatumumab vedotin)、替-伊莫单抗(ibritumomab tiuxetan)、伊戈伏单抗(igovomab)、imab362、imalumab、英戈土珠单抗(imgatuzumab)、拉-英达西单抗(indatuximab ravtansine)、indusatumab vedotin、inebilizumab、伊珠单抗-奥佐米星(inotuzumab ozogamicin)、英妥木单抗(intetumumab)、伊匹木单抗(ipilimumab)、英妥木单抗(iratumumab)、isatuximab、拉贝珠单抗(labetuzumab)、来沙木单抗(lexatumumab)、lifastuzumab vedotin、林妥珠单抗(lintuzumab)、立鲁单抗(lirilumab)、莫-洛伏珠单抗(lorvotuzumab mertansine)、鲁卡木单抗(lucatumumab)、鲁昔单抗(lumiliximab)、Lumretuzumab、马帕木单抗(mapatumumab)、马格土希单抗(margetuximab)、马妥珠单抗(matuzumab)、米拉珠单抗(milatuzumab)、mirvetuximab soravtansine、米妥莫单抗(mitumomab)、莫加珠单抗(mogamulizumab)、莫希土姆单抗(Moxetumomab pasudotox)、他那可单抗(nacolomab tafenatox)、他那莫单抗(naptumomab estafenatox)、纳瑞特单抗(narnatumab)、奈昔木单抗(necitumumab)、耐西维单抗(nesvacumab)、尼妥珠单抗(nimotuzumab)、奥卡土珠单抗(Ocaratuzumab)、奥法木单抗(Ofatumumab)、奥拉图单抗(olaratumab)、奥纳珠单抗(onartuzumab)、欧土希珠单抗(ontuxizumab)、奥戈伏单抗(oregovomab),莫奥珠单抗(oportuzumab monatox),奥特乐土珠单抗(otlertuzumab)、帕尼单抗(panitumumab)、帕尼库单抗(pankomab)、帕萨土珠单抗(parsatuzumab)、帕曲土单抗(patritumab)、pembrolizumab、帕尼单抗(pemtumomab)、培妥珠单抗(pertuzumab)、皮地利珠单抗(pidilizumab)、平尼土珠单抗(pinatuzumab vedotin)、普拉土珠单抗(polatuzumab vedotin),普立木单抗(pritumumab)、雷妥莫单抗(racotumomab)、雷德图单抗(radretumab)、雷莫芦单抗(ramucirumab)、利妥木单抗(rilotumumab)、利妥昔单抗(rituximab)、罗妥木单抗(robatumumab)、sacituzumab govitecan、奥马珠单抗(samalizumab)、司瑞斑图单抗(Seribantumab)、西罗珠单抗(sibrotuzumab)、司妥昔单抗(siltuximab)、sofituzumab vedotin、他珠单抗(Tacatuzumab tetraxetan)、tarextumab、替妥莫单抗(tenatumomab)、替妥木单抗(teprotumumab)、tetulomab、替加珠单抗(tigatuzumab)、托西莫单抗(tositumomab)、托维图单抗(Tovetumab)、曲妥珠单抗(Trastuzumab)、曲美木单抗(tremelimumab)、西莫白介素单抗(tucotuzumabcelmoleukin)、ublituximab、utomilumab、vandortuzumab vedotin、伐提克图单抗(vantictumab)、vanucizumab、varlilumab,维西库单抗(vesencumab)、伏洛昔单抗(volociximab)、伏妥土珠单抗(vorsetuzumab mafodotin)、伏妥昔单抗(votumumab)、扎芦木单抗(zalutumumab)和扎土希单抗(zatuximab)。
以下实施例说明了本发明组合物和方法的实施方案。提供这些实施例是为了举例说明的目的,不应被认为是对本发明组合物和方法的范围的限制。
实施例
实施例1
使用CRISPR/Cas9技术产生携带Rhbdf2基因中的点突变p.P159L的NSG-BALDP159L小鼠。通过前核显微注射Cas9mRNA、截短的导向RNA(sgRNA)和单链寡核苷酸DNA(ssDNA:
)来靶向NSG胚胎中的Rhbdf2基因座,以将SEQ ID NO:1的第159位氨基酸处的脯氨酸突变为亮氨酸。加下划线的密码子CTA是被引入到基因组中的突变密码子。图1示出了小鼠iRhom2(SEQ ID NO:1)的示意图。
用于产生小鼠(17聚体)的sgRNA:G CAG ATT GTG GAT CCAC(SEQ ID NO:7)
CRISPR/Cas9方案:
1.开启PCR仪和离心机——关闭盖子,将温度设定为4℃。
2.RNAase-Zap(工作区域)。
3.将以下从-80℃取出至冰上(在底架正前面的带标记的盒子中)
a.sgRNA
b.Cas9mRNA
4.在4℃下,以20,000x g离心导向RNA和Cas9mRNA 15分钟
5.将每个样品的顶部液体除去,如下配置sgRNA和Cas9mRNA的稀释液——
a.4μL Tris/EDTA(TE)+4μL导向RNA。
i.充分混合,然后Biospek 2μL(程序=RNA 1mm)。
ii.计算加入多少体积的IDTE至剩余的6μL以使sgRNA的终浓度为300ng/μL,并使Cas9mRNA的终浓度为500ng/μL。
iii.在加入TE进行稀释后,充分混合(涡旋,快速离心)。
6.将以下在PCR管中合并:
a.16.25μL TE
b.3.00μL Cas9mRNA
c.1.25μL sgRNA
d.混合,快速离心,放置于PCR仪中并进行“复性”程序(在RNA文件夹下)
7.稀释质粒至浓度为125ng/μL
a.2μL TE+5μL质粒
i.充分混合,然后Biospek 2μL(程序=DNA-1mm)。
ii.计算加入多少体积的TE至剩余的4μL以使质粒的终浓度为125ng/μL。
iii.在加入IDTE后,充分混合(涡旋,快速离心)。
8.将RNASin稀释10倍(lμL,于9μL IDTE中)
9.复性完成后,将样品移至冰上。一旦冷却,将样品涡旋混合并快速离心。
10.最后,加入稀释的质粒(2μL)和RNASin(1.25μL)。体积此时应该是25μL。混合并快速离心,然后将20μL转移至新管中。为显微注射到小鼠受精卵中,首先将DNA/RNA材料注射到前核中,然后在退针时注射到细胞质中。
共有16只幼仔出生,并且令人惊讶的是,16只幼仔中的8只显示出部分(95%或更多)至完全(100%)毛发脱落。将获自幼仔尾细胞的DNA使用PCR扩增、纯化、测序以鉴定并确认哪些幼仔携带p.P159L突变。
使用以下测序引物来鉴定点突变:
正向:ACACACACATGTACCGCCAT(SEQ ID NO:8)
反向:TTCTGGCCTTTAGGGTGTGC(SEQ ID NO:9)
表I中示出了PCR循环条件:
用于PCR产物的磁珠纯化方案
*典型步骤:15μL PCR+3μL 6X染料->在凝胶上运行8μL,纯化剩余的10μL
1.加入18μL充分混合的小珠(比率=1.8μL珠/lμL PCR产物)。
2.充分混合,然后快速离心(持续尽可能短,只需将液体倒掉,不希望使小珠沉淀/聚集)。
3.在RT下静置至少5分钟。
4.放在磁铁上,静置至少2分钟。
5.通过向每个样品中加入100μL 70%乙醇来洗涤。倒置在纸巾上。
再重复至少两次,或直到上样染料的所有迹象都消失。
6.少量乙醇将留在底部。最后一次洗涤之后,使用带过滤器的凝胶加样移液管枪头将乙醇尽可能多地移除,同时保持小珠完好无损。
7.使乙醇从样品中蒸发,同时在磁体上静置,通常持续约10分钟。
8.从磁铁上取下,检查乙醇是否完全蒸发,然后加入40μL水。充分混合,然后快速离心(再一次,尽可能短)。
9.将样品放回磁铁上,静置至少2分钟。
10.使用凝胶加样移液管以避免与小珠接触,移出25μL(或更多,如果可移出而不使小珠与样品一起的话)至新管中。
11.经纯化的样品此时可用于测序(5μL纯化样品+1μL 5μM测序引物)。如果需要,可将样品在凝胶上运行以确认纯化是成功的。
如图2所示,测序结果将野生型小鼠与p.P159L突变杂合型的突变小鼠区别开。将携带p.P159L突变的建立者小鼠(founder mouse)与NSG小鼠回交(NI)以检查是否通过种系传递产生突变小鼠。将所得的Rhbdf2P159L等位基因杂合型的后代(N1F1)相互杂交以产生纯合的Rhbdf2P159L小鼠。Rhbdf2P159L等位基因纯合型的小鼠的特征在于无毛表型。Rhbdf2D158N等位基因纯合型的小鼠的特征在于无毛表型。Rhbdf2I156T等位基因纯合型的小鼠的特征在于无毛表型。Rhbdf2D158N、Rhbdf2I156T、Rhbdf2P159L等位基因中的任意两个或多个纯合型的小鼠的特征在于无毛表型。
毛发脱落在NSG-Bald小鼠中清楚可见并且在6天龄时发生。图3示出了携带Rhbdf2p.P159L突变(NSG-Bald)并以无毛表型为特征的6周龄小鼠(左)和携带野生型Rhbdf2等位基因的正常白毛同窝幼仔对照小鼠(右)。
使用替代的寡核苷酸利用类似的程序来产生具有突变iRhom2的其他遗传工程NSG小鼠——所述突变iRhom2包括在SEQ ID NO:1的第156位异亮氨酸处的突变、在SEQ ID NO:1的第158位天冬氨酸处的突变和在156、158和159处的两个或三个突变的组合,产生了经遗传修饰的NSG小鼠,其中所述小鼠的基因组包含突变的Rhbdf2基因,所述小鼠表达突变的iRhom2蛋白,并且以无毛表型为特征,如表II所示。
在NSG-BALD小鼠中的异种肿瘤细胞植入
从ATCC(HTB-77)获得SKOV3人卵巢癌细胞并将其在RPMI培养基中培养。向6-8周龄的NSG-BALD和NSG雌性小鼠(n=10)腹膜内注射悬浮于200微升PBS中的0.5×106个细胞。监测体重和肿瘤生长50天,在研究阶段结束时进行尸体剖检,将肿瘤样品固定在10%NBF中,并用石蜡包埋以进行H&E染色。
统计学分析
使用GraphPad Prism产生Kaplan-Meier存活曲线。小于0.05的P值被认为是显著的。
实施例2
动物
使用六至八周龄的NSG-BALDP159L(n=5)和NSG雌性小鼠(n=4)来检查肿瘤生长。在Jackson实验室饲养小鼠并使其保持在无特定病原体(SPF)的条件下。随意提供食物和酸化水。
异种肿瘤细胞制备和给予
将MDA-MB 231人乳腺癌细胞在RPMI培养基中培养并在37℃下生长。将悬浮在200μL PBS中的MDA-MB 231人乳腺癌细胞(3×106)经皮下注射到NSG-BALDP159L和NSG小鼠中。
肿瘤大小
使用外部卡尺每天测量皮下异种移植肿瘤直径。为了通过外部卡尺确定肿瘤体积,使用外部卡尺测定最大纵向直径(长度)和最大横向直径(宽度)。然后将肿瘤体积计算为:1/2(长×宽2)=肿瘤体积。在研究结束时,收集肿瘤并进行组织学分析。
肿瘤生长
使用下式计算肿瘤生长:[给定日的肿瘤体积/第7天记录的肿瘤体积]×100=肿瘤体积增加百分数。
统计学
将数据表示为平均值±平均值的标准误差(SEM),并使用Student'st检验计算NSG小鼠和NSG-BALDP159L小鼠之间的生长的差异。小于0.05的p值被认为是显著的。早在第18天就观察到肿瘤生长的显著差异。
结果
图4是示出了植入到NSG小鼠(下面的线)和NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ(NSG-BALDP159L)(上面的线)动物中的人乳腺肿瘤细胞系MDA-MB 231生长的图。与对照NSG小鼠相比,NSG-BALDP159L(上面的线)小鼠中的MDA-MB 231人乳腺癌细胞肿瘤的生长显著更快,所观察到的NSG-BALDP159L小鼠中的肿瘤体积增加是NSG小鼠中的约两倍。
对NSG(图5A)和NSG-BALDP 159L(图5B)小鼠中的MDA-MB 231人乳腺癌细胞衍生肿瘤的血管标记物CD31进行免疫染色。与NSG小鼠的异种肿瘤相比,在获自NSG-BALDP159L小鼠的异种肿瘤中观察到强的CD31免疫组织化学染色,表明在NSG-BALDP159L小鼠中异种肿瘤中的血管化增加。不受理论因素的限制,应理解,异种肿瘤中血管化的增加可支持根据本发明的方面的遗传工程免疫缺陷小鼠中增加的肿瘤生长,所述小鼠表达具有一个或多个选自p.I156T、p.D158N和p.P159L的突变的iRhom2蛋白。
实施例3
如对SEQ ID NO:1和3进行比对的图6所示,小鼠iRhom1和小鼠iRhom2是高度相关的蛋白。鉴于小鼠iRhom1和小鼠iRhom2的高度结构同一性,进行研究以确定iRhoml中的修饰的功能效果是否类似于在iRhom2修饰中所观察到的功能效果。
产生Rhbdf1敲除C57BL/6小鼠,产生了iRhom1缺陷型小鼠,并发现iRhom1缺陷导致体重减轻。图7显示了大小正常的Rhbdf1基因缺失杂合型(Rhbdf1+/-)的小鼠(右)与由于体重减轻而更小的Rhbdf1基因缺失纯合型(Rhbdf1-/-)的小鼠(左)之间的大小差异。
Rhbdf1敲除C57BL/6小鼠死于3-4周龄,如图8中通过图所示出的。Rhbdf1基因缺失杂合型(Rhbdf1+/-)的小鼠显示出正常的存活百分数(图8中图的上面的线),并且是可存活且可育的,而Rhbdf1基因缺失纯合型(Rhbdf1-/-)的小鼠死于3-4周龄(图8中图的下面的线);
Rhbdf1敲除C57BL/6小鼠的特征在于严重的心脏纤维化。经切片并用苏木精和伊红染色的Rhbdf1敲除C57BL/6小鼠的心脏显示出严重的心脏纤维化(在图9用“O”标记的),这导致这些动物在约3-4周龄时死亡。相比之下,Rhbdf1-/+杂合小鼠没有显示心脏纤维化,如图10所示的从Rhbdf1-/+杂合小鼠分离的心脏的苏木精和伊红染色切片的图像中所示。
此外,由于Rhbdf1敲除小鼠在出生后不久就死亡,不可能在这些小鼠中生长肿瘤。另外,Rhbdf1敲除C57BL/6小鼠没有表现出无毛表型,其具有完全包覆的毛发。因此,令人惊讶的是,尽管小鼠iRhom1和小鼠iRhom2具有高度相关性,与这些蛋白质变化相关的表型并不相似。
项
项1.一种经遗传修饰的免疫缺陷小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于在N-末端区域中的一个或多个突变而与野生型小鼠iRhom2蛋白不同,并且其中所述小鼠的特征在于无毛表型。
项2.项1的经遗传修饰的免疫缺陷小鼠,其中所述小鼠具有严重联合免疫缺陷。
项3.项1的经遗传修饰的免疫缺陷小鼠,其中所述小鼠具有IL2受体γ链缺陷。
项4.项1-3中任一项的经遗传修饰的免疫缺陷小鼠,其中所述小鼠包含scid突变。
项5.项1-4中任一项的经遗传修饰的免疫缺陷小鼠,其中所述小鼠是scid突变纯合型的。
项6.项1的经遗传修饰的免疫缺陷小鼠,其中所述经遗传修饰的免疫缺陷小鼠是NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ小鼠,所述小鼠包含突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于在N-末端区域中的一个或多个突变而与野生型小鼠iRhom2蛋白不同,并且其中所述小鼠的特征在于无毛表型。
项7.项1-6中任一项的经遗传修饰的免疫缺陷小鼠,其还包含异种肿瘤细胞。
项8.项1-7中任一项的经遗传修饰的免疫缺陷小鼠,其还包含人肿瘤细胞。
项9.项1-8中任一项的经遗传修饰的免疫缺陷小鼠,其中所述N-末端区域中的一个或多个突变是iRhom2的N-末端区域中的一个或多个突变,其选自第156、158、159位氨基酸或其中两个或更多个处的置换。
项10.项1-9中任一项的经遗传修饰的免疫缺陷小鼠,其中所述N-末端区域中的一个或多个突变是iRhom2的N-末端区域中的一个或多个突变,其选自第156、158、159位氨基酸或其中两个或更多个处的缺失的。
项11.项1-10中任一项的经遗传修饰的免疫缺陷小鼠,其中所述N-末端区域中的一个或多个突变是iRhom2的N-末端区域的全部或部分缺失。
项12.项1-11中任一项的经遗传修饰的免疫缺陷小鼠,其中所述小鼠是Rhbdf2基因中的突变或缺失纯合型的。
项13.项1-12中任一项的经遗传修饰的免疫缺陷小鼠,其中突变的iRhom2的第374-827位氨基酸与野生型iRhom2蛋白相同或基本相似。
项14.项1-12中任一项的经遗传修饰的免疫缺陷小鼠,所述小鼠在Rhbdf2基因的N-末端区域中具有突变或缺失并且表达相应的突变iRhom2,其中与表达相应的野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述小鼠的特征在于增加的外源肿瘤生长。
项15.一种产生用于异种肿瘤细胞的反应的小鼠模型系统的方法,所述方法包括:提供根据前述任一项的经遗传修饰的免疫缺陷小鼠;并将异种肿瘤细胞给予至所述经遗传修饰的免疫缺陷小鼠。
项16.一种鉴定抗肿瘤组合物的方法,所述方法包括:提供根据前述任一项的经遗传修饰的所免疫缺陷小鼠;将异种肿瘤细胞给予至所述经遗传修饰的免疫缺陷小鼠;将测试物质给予至所述小鼠;测定所述异种肿瘤细胞的反应;和将述反应与标准进行比较以确定所述测试物质对异种肿瘤细胞的作用,其中所述测试物质对异种肿瘤细胞的抑制作用将所述测试物质鉴定为抗肿瘤组合物。
序列
小鼠iRhom2蛋白序列:SEQ ID NO:1
小鼠Rhbdf2基因序列:(粗体表示外显子;加下划线的表示第156、158和159位氨基酸的密码子)SEQ ID NO:2
小鼠iRhom1蛋白序列全长SEQ ID NO:3
应认识到,为清楚起见而在多个单独的实施方案的上下文中描述的本发明的某些特征也可在单个实施方案中以组合的形式提供。相反地,为简单起见而在单个实施方案的上下文中描述的本发明的多种特征也可分开地或以任何合适的子组合的形式提供。
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,其程度如同每一篇单独的出版物被具体地并且单独地指明以引用的方式纳入本文一样。
本文所述的组合物和方法目前代表优选的实施方案,其为示范性的且不意欲对本发明的范围进行限制。本领域普通技术人员会了解其中的改变和其他用途。可做出这类改变和其他用途,而不偏离如权利要求中所阐述的本发明的范围。
序列表
<110> Jackson实验室
<120> 与肿瘤分析相关的组合物和方法
<130> JLA-11552/47
<150> 62/248,417
<151> 2015-10-30
<160> 9
<170> SIPOSequenceListing 1.0
<210> 1
<211> 827
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 1
Met Ala Ser Ala Asp Lys Asn Gly Ser Asn Leu Pro Ser Val Ser Gly
1 5 10 15
Ser Arg Leu Gln Ser Arg Lys Pro Pro Asn Leu Ser Ile Thr Ile Pro
20 25 30
Pro Pro Glu Ser Gln Ala Pro Gly Glu Gln Asp Ser Met Leu Pro Glu
35 40 45
Arg Arg Lys Asn Pro Ala Tyr Leu Lys Ser Val Ser Leu Gln Glu Pro
50 55 60
Arg Gly Arg Trp Gln Glu Gly Ala Glu Lys Arg Pro Gly Phe Arg Arg
65 70 75 80
Gln Ala Ser Leu Ser Gln Ser Ile Arg Lys Ser Thr Ala Gln Trp Phe
85 90 95
Gly Val Ser Gly Asp Trp Glu Gly Lys Arg Gln Asn Trp His Arg Arg
100 105 110
Ser Leu His His Cys Ser Val His Tyr Gly Arg Leu Lys Ala Ser Cys
115 120 125
Gln Arg Glu Leu Glu Leu Pro Ser Gln Glu Val Pro Ser Phe Gln Gly
130 135 140
Thr Glu Ser Pro Lys Pro Cys Lys Met Pro Lys Ile Val Asp Pro Leu
145 150 155 160
Ala Arg Gly Arg Ala Phe Arg His Pro Asp Glu Val Asp Arg Pro His
165 170 175
Ala Ala His Pro Pro Leu Thr Pro Gly Val Leu Ser Leu Thr Ser Phe
180 185 190
Thr Ser Val Arg Ser Gly Tyr Ser His Leu Pro Arg Arg Lys Arg Ile
195 200 205
Ser Val Ala His Met Ser Phe Gln Ala Ala Ala Ala Leu Leu Lys Gly
210 215 220
Arg Ser Val Leu Asp Ala Thr Gly Gln Arg Cys Arg His Val Lys Arg
225 230 235 240
Ser Phe Ala Tyr Pro Ser Phe Leu Glu Glu Asp Ala Val Asp Gly Ala
245 250 255
Asp Thr Phe Asp Ser Ser Phe Phe Ser Lys Glu Glu Met Ser Ser Met
260 265 270
Pro Asp Asp Val Phe Glu Ser Pro Pro Leu Ser Ala Ser Tyr Phe Arg
275 280 285
Gly Val Pro His Ser Ala Ser Pro Val Ser Pro Asp Gly Val His Ile
290 295 300
Pro Leu Lys Glu Tyr Ser Gly Gly Arg Ala Leu Gly Pro Gly Thr Gln
305 310 315 320
Arg Gly Lys Arg Ile Ala Ser Lys Val Lys His Phe Ala Phe Asp Arg
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Lys Lys Arg His Tyr Gly Leu Gly Val Val Gly Asn Trp Leu Asn Arg
340 345 350
Ser Tyr Arg Arg Ser Ile Ser Ser Thr Val Gln Arg Gln Leu Glu Ser
355 360 365
Phe Asp Ser His Arg Pro Tyr Phe Thr Tyr Trp Leu Thr Phe Val His
370 375 380
Ile Ile Ile Thr Leu Leu Val Ile Cys Thr Tyr Gly Ile Ala Pro Val
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Gly Phe Ala Gln His Val Thr Thr Gln Leu Val Leu Lys Asn Arg Gly
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Val Tyr Glu Ser Val Lys Tyr Ile Gln Gln Glu Asn Phe Trp Ile Gly
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Pro Ser Ser Ile Asp Leu Ile His Leu Gly Ala Lys Phe Ser Pro Cys
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Ile Arg Lys Asp Gln Gln Ile Glu Gln Leu Val Arg Arg Glu Arg Asp
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Ile Glu Arg Thr Ser Gly Cys Cys Val Gln Asn Asp Arg Ser Gly Cys
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Ile Gln Thr Leu Lys Lys Asp Cys Ser Glu Thr Leu Ala Thr Phe Val
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Lys Trp Gln Asn Asp Thr Gly Pro Ser Asp Lys Ser Asp Leu Ser Gln
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Lys Gln Pro Ser Ala Val Val Cys His Gln Asp Pro Arg Thr Cys Glu
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Glu Pro Ala Ser Ser Gly Ala His Ile Trp Pro Asp Asp Ile Thr Lys
530 535 540
Trp Pro Ile Cys Thr Glu Gln Ala Gln Ser Asn His Thr Gly Leu Leu
545 550 555 560
His Ile Asp Cys Lys Ile Lys Gly Arg Pro Cys Cys Ile Gly Thr Lys
565 570 575
Gly Ser Cys Glu Ile Thr Thr Arg Glu Tyr Cys Glu Phe Met His Gly
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Tyr Phe His Glu Asp Ala Thr Leu Cys Ser Gln Val His Cys Leu Asp
595 600 605
Lys Val Cys Gly Leu Leu Pro Phe Leu Asn Pro Glu Val Pro Asp Gln
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Phe Tyr Arg Ile Trp Leu Ser Leu Phe Leu His Ala Gly Ile Val His
625 630 635 640
Cys Leu Val Ser Val Val Phe Gln Met Thr Ile Leu Arg Asp Leu Glu
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Lys Leu Ala Gly Trp His Arg Ile Ser Ile Ile Phe Ile Leu Ser Gly
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Ile Thr Gly Asn Leu Ala Ser Ala Ile Phe Leu Pro Tyr Arg Ala Glu
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Val Gly Pro Ala Gly Ser Gln Phe Gly Leu Leu Ala Cys Leu Phe Val
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Glu Leu Phe Gln Ser Trp Gln Leu Leu Glu Arg Pro Trp Lys Ala Phe
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Phe Asn Leu Ser Ala Ile Val Leu Phe Leu Phe Ile Cys Gly Leu Leu
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Pro Trp Ile Asp Asn Ile Ala His Ile Phe Gly Phe Leu Ser Gly Met
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<210> 2
<211> 30055
<212> DNA
<213> 小家鼠(Mus musculus)
<400> 2
acagaagcag gcagatctct gagttcaagg atagtctggt ctacagggca agttccaaga 60
ctagacagag aaaccctgta tggaaaaaca aacaaacaaa caaaaaagtt gcaggccagc 120
tgggcgtgct ggttcacatc tttaacctca gctcccagga ggcagaggca gagacaggtg 180
aatctctgtg aatttgagac cagtctgggc tagatagtaa attccaggcc agccaaggct 240
acatagtgaa actttgtctc aagacaagat aagggaataa aaaaatattc aagccagtct 300
gctttacaga gcaaagtact gtctcaattt tttcagtatt tatttcaatt ttttacagtt 360
ttttttaagt tataaaaaca tagcaagtgt atgcattcca ctttttgttt ttctactcaa 420
gggcattttg gagataattc cctatcaaca cacagttacc tcattgcttt taacagctgc 480
aatgtgacat tcccacacgt tacacccaac tgtttctcac tctcccacac caggcaggag 540
aggtggttta ctgcagccaa gtctgtgatc tctccatctc cagggctagg gcggcatggc 600
acaagtctct gatgtcaccg aagcatcatg catattctcg tccttggccg tacaggggtg 660
aggacacagc ccagccgtcc agcagtgagg acacagccca accgtccagc agtgaggaca 720
cagcccagcc cagcccagcc caggtgccag agtagcatct gccaggctga gaggtggatt 780
gggcctgaat ggttccagca gccccacggt gcctcttctg cctgatgctc tttgctgcca 840
tgggacagac agaatgatcc tcacatgatg gaactcacac gcatgccagg caagtccagc 900
ctcccacctg caccccaacc cccagggctg gttcttttgc cgctctcagc atggtttcct 960
aaggatatgt ggaggggtca ctaaatggct ccctgcctgt gcttcagaga aacagctccc 1020
aagtttgggg ttattatctg tctttgcccc agccttgcct ttccgtggct ggagactggg 1080
aaggagaagt ttgccaccct gcctaatagg aagtaactaa agctctaagc atgtggtgca 1140
cacacatttt atttatttat ttttacatga attagtgttt tgcctgtgtc atatatgtat 1200
gtatgtatgt atgtatgtat gtgttaagta tgtattatga tgtacatgcc tgtggaggta 1260
taagaagggc atttgatctc tgaaactgag ttaaggctgt ctgcaagatc ccaagtgcat 1320
gctgggaact gaacctgggt ctctgcaaca tcagcaaaag cttccaacca tataattatt 1380
tcccctgccc cacttttttt tttttttttt taagatttat ttattgccgg gcagtggtgg 1440
cacacacctt taatcccagc acttgggagg caggaggatt tctgagttgg aggccagcct 1500
ggtctacaga gtgagtttca ggacagccag ggctacacag agaaacacta tcttgaaaat 1560
aaaaaaataa aataaatttt aaaaattctt ttatttatat gagtccacta tagctgtcag 1620
acacaccaga agagggtatc agatcccatt acagatggtt gtgagccacc atgtggttgc 1680
tgggagttga actcaggacc tctggaagag cagtcagtgc ttttaacctc tgctctaccc 1740
aacccaccaa cgtggcagac tgggggcagg gtggttaaga gcaacaagag cccagagacc 1800
tggctcacct ctgaaagcag ctctgctgca gcgccccctg gtggtggtct ctccatactc 1860
tctggctggg cgaggacttc agaaagaaag actgaggcca ttggtgcagg ggctgaggat 1920
agggactcca gacctggggg tacaggtcta gttcgttcct ctgccatttc ctgcctgccg 1980
taagtttcca catcaaatcc caagtgaggg gctaacccag gccctaggca tctgtatcag 2040
tggcaccccc tgcccttctc cggcctgctg ttcttgttca ggagctgaca ggtccggcga 2100
gtgctcgtag gtgggagcat gggagtgttg gacagggtgt cataaatgta ggccttcgta 2160
cagggctagg tacgcgaaca tgaagagtgg tactctacca ggaagtgggt aagaacatca 2220
caagatggca ccacccagag ccgagttaag ggagggatat ctgggtccag gagggagatg 2280
aggaggcaca gcccagctcc tatgggctca aggtggctag agacgtgggc taaggaggat 2340
aaaagcctgt ggcttaaact tgagggaggg ccggccgtca ccactactaa taatagcaaa 2400
gataacagca gctgctagtt agagccaggg gccccacaaa tgctccctgt tactgctacc 2460
acacagagag gggaaagctg agaccgagga ggcttagggg attcatctaa gaccacagga 2520
gcagtcaatg gcagatcagg atttgaaccc ccggctctgt tagctggagt catatatagt 2580
tatttctcat tacagccaac aaagcaagtt acttggtcag tattggccag gctagagtat 2640
ccaaagcctg ggcctggggg ctgttcatga cacggagatg tggagggcct tcctctgcat 2700
ctattgccag ttactgtgag agccagcttt cagccttagc aagaagcctc tgtgtccttg 2760
ggtgcagagc aacattcaca gtttcctaag ggacagtccc aagaactagc atatacctcg 2820
gttgcctttc caactgctct gtgtttagtc ctggggtggt taaggggaca agacccaact 2880
tccagcaagg acccggtctg gcctagaagg gatgccaggc ctgaggagag atcattctaa 2940
tggacgaagg agagacagca gctagagaag gccaaggctt cctagacgat gtagctgcag 3000
cgatcgatcg gggattctgg aaaggatgca agcctagtcg aggctcctgg agtcaaagga 3060
gcctgaggtc acacgagaaa gagaagggga aattgagtgg tttttgcttg gttgttatgg 3120
gggtgtgtcc gtgtgagcgc gtgtgttgct ggagatcgaa cctaagatct gtgtgctagg 3180
caagtgttta aatgtggcca taagtggagc agcaggagct acaagcccag gcagaagccg 3240
cgggccgacc acgccccccg aagcaccgcc cacacaccaa gaagccccgc ctcaatgagg 3300
ccccgcccac acccagtccc cgcccctgcg ccctcgcgca ggtagggaag aggcggagcg 3360
ctggcgctca gccttgtagc cgccgccccg ccgctgccca ctctgctctc agccgcttcc 3420
cgggacgtgg ggcctccgag aggtgagcac ggggaattgg gtgcggcgga gctcgggtcc 3480
gctaggccgc gggtggccag ggattcacgg ggctgccccg ttcggccgcg gggaaggtcg 3540
ggggctgtgc gccccgcaga gcgccctaga ggccgaggct ggactctgtg cccgcgggac 3600
cgctggatcc ctcccgcaga tccttggcct ctgctgggac caggacgcct aaaggggttc 3660
cccggggcac agtcaccaga tgtctgggcg cgtggtttgc gcaaaagttt aaaagcccag 3720
agaggaagag agggcactgc ccagtgttgg aacatgcgac tccgcctcca accagaaatc 3780
ccttttagac cttaagacta tattcccctg tctcccgggt gaacttccaa agtcctcggg 3840
cagcgttttg tgcgtggagc ttcgccgccg tggtagtaac aggtgcgggg gtgggggatg 3900
gggaaggctc acaccgccag agtagtccgc ggctcagaaa gtgtactcag gagtcctggc 3960
ttaaggaccg aggggtttgg agagttgggc ccccagctga tgtttctgca ttggattgaa 4020
agttagggag cgaaaggtct gtagggccca ggtctctacc acaaccccag ggcagaaggg 4080
aagccaggtc cataccttga ttcaactcca ggaaacaccg agccgcgagt ctgtagggcc 4140
gggacataga gagcgaaggt gaggtgtacc tgagggattg cctcataggt ggagcggttg 4200
ctgtttctca accagctgca ttgggggttc cagtgtgggt gacatcttgt ggtgaaatac 4260
tgtccccagc atctatgttg tgctgttgtg attgtagtca gggagaagaa aatgaaactt 4320
ggtttcaagc agtggttctc agcttagggg tgcttttgcc cgctaaggat atttgacaat 4380
ccctggagac acttggccat cacaggtctg ccccacagta cagaatctgg cccctcaaaa 4440
gtcaacattg agtgaccgtc ctatgaccac cagcccacta gggtacttct tgtgaatttc 4500
tctccctacc taagtttctc caggggctgg gaagggccag gacgaatctc agtgagagat 4560
aaagagatag gtgggcaggc ttcgccctgg ctggccactg gccctgtgga ggagaagctg 4620
ggaacagtgg ctctctcgaa gcacaggtct gtagtacttt acccaggata gcttcagaca 4680
caggataagc tcaaggtaag ccagagtagc cctggggatg gaggaagggc aggaccaagc 4740
tctgttccca tggagtttcc caaagctgga tgagctgagg tctcccggat agcggaatgc 4800
catgtgacca actggaattt tccttctgaa cacagaactg actcccctag ctatttacac 4860
caggaaagta acatccaagg aataacgggt ccactgattc cctgtggctc ctctctttcc 4920
ttccaacagg atgggttgcc cctggggcgg taggaatcct ggtcagggtg agctcaggcc 4980
ctgctgtagt atttgctgag tgacagtaaa ggatggaggc tggtaaagag ctttccaccc 5040
acggggtccc ccaaaaccgc ggagttgggc tcctgggctg tactcttagc tttctgggaa 5100
tggaggtgag gctgttgctg gctgggtagg tcagggccag aatcctctct tccggcaact 5160
aacatttcca tctccctttg tcctgtctag ttttggacac ttcttgcttg agagccctgg 5220
tggggtgaga agggagtggt gggactgggg gcggggcagg agtctcgggt tggttggttg 5280
gttgattgat tttggtcttt ttaaccataa aaccctgatg tgtagctaga cttggtggtg 5340
tgtgctttga tgtcccagca ttggcaggta gtggcaggag agtcaagagt ttgtcaccct 5400
cagtaacaga gtgagtttga ggccagtctg ggctctacaa gaccctgtct cagaaaccca 5460
gcagaagacc agacctttac aatgtagcag ttaccactac tgtatatggc tctgaagtca 5520
taaagttaaa cacccagacc tcctcaaagc cacctacccc aaacctgtaa ctctagcttc 5580
actcgctcat tctggtcagt gcccaccccc acccccaccc tttctataca cgctgctgcc 5640
aggggagggg aggagacttc caaaagagca ggggtaaatc accccagact ggagcaggac 5700
gaccactggg ggctcaggcc tactctgggc tcactgatgt ttttcttgtg acctgagctc 5760
tggacagtgc cctccttggt tgtgtgtctg ttcagcttgt gtgtgcggga tgcttgctaa 5820
cccccccccc cccaatctgg aattacagac agttgccagc tgccctggaa atgctaggaa 5880
ccagtctggg ccctttagaa gagcacccgg tgctattaac tgctgagcca tctctctagc 5940
tccatgactt gtataaactg tgtcccagac aggcaccaga tgacagcagg aagatgtcaa 6000
ggggccggca agtgttcatg tttgtgtttg ggtaacttga tgctggcttc tgggcctgga 6060
tccccttaca cagcatgtgg gaggtgtgtt ctccctgccc caatccagca tgttccttgg 6120
aactcatggg atcctgccta gatattgccc cattgctcaa ggggatttcc aaagtgacct 6180
caccatctgt gccgttggga gcagctccta gtttcctatc cagctcagac aggctggggg 6240
aggagtgctg gctgacctca gcagccagca tggccctggg acagggacgc tgccaggccg 6300
ggcagctctt ggcacacagg caacctctca agaggagcca gccacgcctg ccccgttgtt 6360
gggaggaagg gactgcccca aagtgtccct ggccttccca ggcagcagac cagcataagg 6420
gaaatctctt ctcatcttca gagagctatg gagagtcact gggcaccatg ctcccttcac 6480
cagatttatt cagggaccca gatgtaagca tttgggtttc agcagctgct gaaagggact 6540
gtcagcttca ctgtcctggc tccccgctta gtggtttgag ccaagtgagt tctggcaggg 6600
tgtgggatga tagacaccat ggttggctag aggggcaggt gattccgcgc tcaaggccca 6660
ggagggacgg tcctggggcc agcagacttg agtctgcaag aagggtgggg gtcacttgag 6720
taggcttgcc tcagtttcta catagctgtg tagtggagtc atttaagtag actaaccttg 6780
gtttctccac tataccgcgg aggattgagg tggcctgtgg acatgtgggt gtgactggtg 6840
gagatactga aatgagccat cattgcagca agaccgctgt gcctggcaca ggcttgggtc 6900
atgggagaaa ccctgcctcg taggctgctg ggatatcaga acagaaagca tgtcagggtg 6960
atctgaactc tacaaggagc agtttctgcg gtagagaacc ccctggggct gggagtgagc 7020
gttttattgc aaagccctgc tcccctgcct cagtaggtgg ccactgaacc catgtccaca 7080
gtgtcacggt gatgtagggg agctacccgc ccctggtccc tggcacaggg tgccttttcc 7140
ctctccaggt gggtccctga agggtgcaga acctgttgtg gtattctggg tagacacacg 7200
actgaaaact gagggctcag ctgggccctt agggacttta tctgtcaggc tgcataatga 7260
cagtggcctc cgccctccct cagttaatga gataatgctt gtgaaagctc tctgatagct 7320
gagtggctac accggcagta ggtgttgcca ctcctcgatc ctcgtggatg ctagaggaaa 7380
gctttctgga gccgaaggca tttgcacccc aactacacag atggagcagc cactctagac 7440
acgccctttt gccgcttggc ttttcatgtt tcaagagggg taggtttaag aactagtgga 7500
gagccggctc aggggctgag agcacactag ctgctcttgc agaggacttg gattcaattc 7560
ccagcaacca catgctggtt tgcaaacatc tgacattctg tttccagggt acccaacact 7620
ctcccctggc ctccacggac actgtacgtg gggtatagaa atacacacag ataaaaatac 7680
ctgtacacac agagaaaaaa aaaataaaag taattcttta aaatataaaa aaaacctcag 7740
gacccaagca ggctacagcc ccagcgcctc cggaggtagc gcagagactg aacatcagtg 7800
agccttgatt tataactcaa actgtcaggg agaatcttgt cacgtggctc ttggctcgta 7860
ggctgagtgg gtgggtcatg gtgccaaggg ggaaaagcca ttagttagct actgctggtg 7920
cacccggcat tgtacatgca ggatctgcct gccatccatg tagtgactgt caccccatct 7980
cacagaggaa accgtgacag accacacgtg agccttgact ctgactccca gcatgccatg 8040
agagtcctac actgccccaa agtagcagat agcattgaag gttcacctgc tgtgggcaca 8100
gcttggatgg ccctgtgtcc aagttccctt ggcacccact gtgaccggga ccagccgctt 8160
cctggggaag tagggtgccc cagggcagag ttctggaaaa tcaagtttat tagcttctta 8220
atgacggttt acaagccaaa aagtgtttag ctggcgtgtt cccttcctgc tgagaggcat 8280
caaccctgca gaaggagatc tgggcaggat gccgagcgcc ctgtcctgag tatgctgagg 8340
aaaacatctc agggcaacct gcaatccttt ggtgctttag agcgctcata cctgacctgg 8400
acactgcctg tttctggctg aaggacccac actatgcaag gactctgtag gatagggtga 8460
gactttgtcc ctcagtggaa catgctgtat gatagatgag ccctagttat tggtgacaga 8520
aacacccagg tctcaagagc ccacataaac aacacattga gttagaggta ttaagtagct 8580
tgctcacaat cacacagtaa agctggcccc gtgaccctgc ttctcctagt caggcagttc 8640
ctatctctgt agccacgctc caagatggcg gatggaaatt gggtgggcga ttggcttgcc 8700
agtatcaggc gaaaccccag ctgtgtggtg tgtcacatct tggtgtcagg gaagcctaga 8760
gaaataaaat caccacgtta ctcagccttc cctgcaccca ccccctccca ggctacaccg 8820
catcctgccc tgaccactgg gactgtactc ttctggtttt gaagactgat gaaaacccaa 8880
ttcccagtag ccaatgttcc tatgacaggc agagcttcca tatgaaagca agctcatgtt 8940
gatgtggtgc ccagggtaaa ccgctccctc tgtgggagcc tcctttgacc tggcgtcttg 9000
acccccaggg aggggcagca gaagtgggac agaatatata gtcttctctg gagaccagac 9060
ggctagacaa gcagcctaga acccagccgc ctattggctg tctctgtact gttccctaaa 9120
gctgtggtca gcatcccagc ctgcagccct gccacatgac ctgctgttgc tgcctgaggt 9180
gtgagagggc tcagttctac tcagagcacc tgcatctctg tgactggagg ggacatgcct 9240
cgccagcagc ttctagagtc atgaagtttc cagaggagct ttgagctgca gctcctagct 9300
gcatacccat ttcccagtat gttagcatct tgtgtgtgtg tgtgcgtgtg cgtgtgcgtg 9360
tgtgtgtgta tggaatccaa agccttacgc atgccgagcc agctttctgc tactgagcta 9420
cacccatgcc caattgttgt atcttgagct ctggggatac agaacctgtc ccctgcctca 9480
actgctccta ggacaagagt ccccagcaga ggcggaaggc atttgcacct ctgctgatct 9540
ggctggccag tagtccagag aaaggccaga tagatgggga gagggggaac ccgggctgga 9600
cctctctaag agcagggtgg cacacccaca cagacaagct cacatatgct ctgctcttgg 9660
cagctccctg gaacctcgtg cccacttccc gtgcctgtgg tgggccgtga tgcccaagct 9720
gctctagttg ggtcagaggg aaccgagagc gtagggtctg aatgtggaat acccccaaag 9780
aagccagcag gctgccaagt ccttgagcct gctcctgtag gtctggtctt gtgaaataag 9840
tttggcacaa gccctgggaa gaaggggaga atgaagtgag ggctctgtgg gggaggcctg 9900
ttgcttgtga ggtctgtgca gcgtgtgaac ccacaagcca gttttctttt cttgtgggtg 9960
gccaccaggc ctgtgcaggc cagcagagcg tggtgccttg gcatacataa ggctttggat 10020
tccatacagc catacacaca cacacacaca cacacacaca cacacacaca cacacgcgcg 10080
ccacatttgt gctaccacct ttggcccata cctctgagga aaagcacttc aggagcacag 10140
agccctctgt cctttctccg tggtccttgc agcttccatt cgatgcatcc tgctgctaga 10200
ccgcaacccc cccttctgta ttttgtgacc ttttctgggt cctggcccca gacctggcct 10260
cttcacctct ctgcctttgg ctccatcatt cctgcctctt tccagggcca ggagatgctc 10320
tgcagtgagt caccaatttg gagacttctt agatgacagt ctgtcttaca tgggttagcc 10380
ttccacggcc accagggctg tcaagctttg ggaggccagc aacagaaact aactttcttt 10440
ctttctttct ttctttcttt ctttctttct ttctttcttt ctttctttct ttctttcttt 10500
ctttcttagc gggatttcaa cagttgaggg ttccacttcc tctcttcagc tttcgaaaaa 10560
ctcagaggtt cccagcaggg ccacaggagg gaagatgcag ttttggtttc tgtggcaggg 10620
aaaccgggga gagaagttgc ttgcttgccc ccagcccaca ctgtcatcat cctgtgactc 10680
agcaaggaca tggcatatgg tctgtctgcc accaccccct tctctgcccg ctctctgcat 10740
gtcccaggac gtggctgagt gaggcttctg gggcaggtgt agtttattaa gccctctgtg 10800
actcgtaaca cccccctttg gccatatcca gttgtgaata atggtcttcc ccctttccat 10860
ggaggggaga gggctaccca cttcttgtcc attggtccct cctgctgccc acatttctgg 10920
cccatatgtg accttggcta ttacatcagg cgcctgcttg tttgggaata caggctccct 10980
caatgtcctg tttcctcaag tctacagagc ttacgggtgt agggaatcat taataacgct 11040
gggcttccag gatagtgggg gtgcgtcagg tcagacctgt gggtacaggt ctaccccttc 11100
ttggagcaga gagggaggaa tctaagcata tgccacctgc atgggaaggg agggcaccct 11160
gcctagagtg gttgggggag caccccctgg gggtgacctt gcctaccatg ttatcatgcc 11220
tggattggac ctgcctcatt tgggagtggc tgggccccac cctttgtggg gaaaccggat 11280
tctgtgggac attctaggta gtctcagagc ctttgtttct gtgtgcctaa tctgggccac 11340
cactctgtgg gtggtgctat ccggaaggct ctctggagag cacgctgacc cctagtggag 11400
gccatctacc aagggctcct ggggcggggg gtgggggtga gggaggcggg gggtgggggg 11460
gaaatctcag ctttgcactg cattcttctg ctgtctgccc cacccccacc tcttggtaga 11520
caccacccta gaggaagagg aaacactgac acccctccgc cctgggttcc gggtaaatat 11580
tcttgtgaga aagacttctc cctagaagtt agaccaggat ccaacttgag caggtggcag 11640
agaccataat cctggctttg gtccctgtca ctcccaccca tgggccagct gggcagcaag 11700
tctagggtca gagagctcgg cggatatgac tgtgggcaag aggaagcttg ctcccaggat 11760
gtcacaattt cctttgcaat gagcaagcac ctctgggggc gggagataag tggcgggcgc 11820
ggagggcggc tcctgcaatt tttttttttt tttggtctag tttctgtggc ctttcataga 11880
cgtaggtcac acggggggac tagagcaaat ctgatcattc ccaccactgt gccaggcagc 11940
tgccagcccg cccagtccag agaagggttg gactttaccc ccccccccca aggttggggc 12000
agaggggtca ggagaagttc tgggagaaag tatcagagaa aaaccttcat tatccaggct 12060
gtctgtggtc agcaggtctg agccatcacc ttgtccaact gccagtggac aggaagggaa 12120
actgaggcac agggatgtag cttagggacc atcattcaaa gctcggtact ggcttcgcag 12180
atggtggtag agagtttcct ggcacgtgac tccttacagt ctctgaccca cccctgcggt 12240
cggacttctt tctaggggac cctgagattg tcccaaactt cccctgtcct gtggccttaa 12300
gtcatgtctg ccttttccat gtggagattg gttagggggg tggggtggga gggatcctgg 12360
gtatatttgg gggaggggtt gtcaccagct ggaatggcct gggctctagg ggcagctcct 12420
cagaggggta agagtgtttg tggacaacca gggaactagg ccaccaggcc tcatcctcag 12480
ccagcaccca gagacctcca tcccagccct gcagagggac tgggcaaggt gagtgacttc 12540
cagagccaag ttcagagttt gagagacagc ctcagcccag catccatgca gtccgtcccc 12600
agctgcacag actcctgccc tcaccagact catccagcta ggacttgatg ggcagtgatt 12660
gggtgggaga ttagagtaag gggctcctgc tgtcaggagc tgtgggatgc agcgtgagac 12720
agagcagggt ggtgagaggc ttcctggagg tgacacgcct tagaagcgca gtaaatacaa 12780
aggttgctcc cagggcactg gcaaggcagc tgatgcggaa ggcagggtgg catgtcacag 12840
cccggagcct gcacaggtcc tacccctgac acactgccag ccgcatgatc acctagactc 12900
tgagcaacaa gaagacacca gagatgaaca atggttcatt ttctgggtta aggaaagacc 12960
tctgaggtcc atggtctgtg ctgccgccag agaccattgt tacagtctgc cgtccatgtt 13020
atctatgacc attgctgtca ccagaggcca tgtggatgca tgtgaatgtc cctgatccct 13080
ggccaagctt ctgtgggcag aaaagcttcc tctgcagtga tattaatgtc tgtagagtca 13140
taactgagag tgagcgacat tgaggggctt ctgtgacaac cgccccccac ccctgagaga 13200
gagagagaga gggagagaga gagagagaga aaggagctat tgaagagagt ctgtaaaaat 13260
tgtccaggca gtggagcctt taatcccagc actggggagg ctgagccagg tggatctctg 13320
gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgc gcgcacgtgc gcgcgtgtgc 13380
ctttgtgttt tccaggacag cctatctcaa acaaacaaac aaaaagtgat aaagatgcta 13440
agtgtggctc ttcacagttg gtggcttctg gcaggaatgt ggatggggga agactcagtt 13500
ctcttaaggg gctggccact gagagtctga cgatgctcca gtgagtacat gggtaacata 13560
aattgaactt ggtagatgtg gaaggaacac aaggggagaa aggtgttctg gaggcgtggg 13620
aagcgagagg ggtaggaata cattttataa aattcccaaa taattaataa aaatattttg 13680
ttggggaaaa agaagcagca gaggttggcc aggttgacaa ggctggcata agattgcagg 13740
gcctcagaga caggaggtgg gagcttggca gaggtgcagg ggagagatct gggtcttagt 13800
aactgttctc ttgctgtgaa gagacaccat gaccacgcag cttatagaag aaagcatgag 13860
ttgaggagtt gcttacggta tcagagggtg aggccatgac catcatggca gggagcttgg 13920
tagcagcagg catggttgct ggagaagtag gtgaatcttt acattctggt ctgtaggcag 13980
cagacagaca gagaaagaaa caaacctggc ctggtgcagg ctcttgaaac ctcaaagctc 14040
actgccacaa cacacctcct tcgacaaggc cacacctctc aatccttccc aaccagttca 14100
ctgcttcaca cacatgagcc tgtggggcca ttggcattca aaccatgaca gtctggctgg 14160
ctgagtgggg caagccggcc ctgctgactc ctgggcaggg ccttcaactc ctcattccag 14220
aaggctctca tcgctgtcag ctagagagcc acgggcggtg ttctcagggt gcagaaagtt 14280
ggacccatct ctgctggtga ccttctttgc cccccccccc tctctctctc tctctctctc 14340
tgcctgccgt tctcccttgg tgccagtttc tcagagtaat gctctctccc tgcaccctgg 14400
tcccaggcca gttgaggagc ttctatgtgg aggccccagg agaggctgtt gtcctggagc 14460
tctcccctgg cagtgtctac gtgtgactag cagggctcct cagagtctgc cagtccagcc 14520
cctagtgtct tccatctgtg atctcagagg gctgagggac aggactcttg gcatgatgga 14580
gccaaagcta aggcctttgg tcccacttaa agaagcagta atgatctggg cccgctctgc 14640
ctactcccca cctaatgctc tgggtctgta aaatggagag ttttacaggc ctcagtacag 14700
caaagcctag aagggtctgc agatgggatc acctgggcct acagcagccc ctgcttccag 14760
ttctcccatg gtaggccgcc tctgggcagc ctaggcctct gccagtcatg ctttgagagt 14820
cactataatg ctagaccata gctccctgtg tctaagataa gagtcttcca gccccagtgt 14880
accctgactt taggaaagga ggggcccaga ctcctaaggt ggctcacacc cactgtcaga 14940
tgacttggat cctaggggca ccccttccct gctgtgtgag cttggttaag ttaatcaacc 15000
cctctgagcc tacaaatcag atgcatagca acatctcttc tggaaggatt tgaggggcag 15060
tgggtgtgcg tagggctgag cccggcctgc cactcatggc actaattgtg cccggatact 15120
gtaccacttc ccagttgctc ctggagctca ctccaaggag aacctgctgt gctcctgtgc 15180
cttgtttgta gtatacgcct gcacagggct ttctacaaca caggcaccgt ggtgttctct 15240
ttcaaatggt taatgttctg ttgtgtggat tctacatcag taaattatta agaaaaagca 15300
aaaacaaaca aatggcagga ggggtctcca ttgccctagt accaggccac ctcatggaaa 15360
ttaaagtttg tgtttgtagc gctggaggtt gaagccaagg cctcctgaat acgtggaagg 15420
cacctgacat cgagctatag ccttggcccc tttcctttcc tctttcactt gttcacactc 15480
gcatcagtgg ggtgtgtctg tcgtggcgcg ggtagaggcc agaaaacagc ctcgcttgct 15540
gtgtgtacac caggcttcct gcccctaggg cttttgaagg tcctctgtcc cattggaggc 15600
atgtggggtt ccaggtgctg ctgttggtgg gtctgcatgg gttcttcaca cctccatggc 15660
aagcactgta tctactaact caccgctagc tctagaccca gccctttttc catctgtgtg 15720
tgtgtgtgtg tgtgtgtgcg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgta 15780
caaccttggg tgtcgttctc agggatcata cacacacctt tcttgttttc agatagggtc 15840
cctcaatgcc ttggaacttg acctctgggc aaccagcccc atgtatcaat tcctgcctcc 15900
attgatccgg ggctgggatt acaaatccgt aatgccatgc tcagctctgt tgttgttgtt 15960
gctgctgctg ctgcgaataa ggatactgga aatcaaactc aggcctgcgt gttctatggc 16020
aagcatgtta ggactgaccc atctctcgat cctcagaaat cccagcactc gggaggcaga 16080
ggcaggcaga tttctgagtt ggaggccagc ctggtctaca aagtgagttt caggacagtc 16140
aaggctatac agagaaaccc tgtctcgaaa aaaaccaaaa aaaaaaaaaa aaaaaaagaa 16200
gaagaagaag aagtagtcag ggtaaagtag gtgggtcggc gggtaaaagt gcttgtggtt 16260
ggggctggag acatggctga gtggtccagt tcccagcacc tacacggcca ctcacaaaca 16320
ttgtaactcc aattccaggg catccaacgc ccttttcagg cctctgtggg catcaggaat 16380
gcatgtgagg cacgggcata cattcaggca aagcacctac acacgttctt cccaaaagtg 16440
cttgccacgg aggcttgatg agctgctgcc cacaagggag gagagattaa ttaatttttt 16500
aaaaaaagcc aacaacgctg ggcgtggtgg cgcacgtctt taatctcagc acttgggagg 16560
cagaggcagg tgaatttctg agttcgaggc cagcctggtc tacaaagtga gttccaggac 16620
agccagagct acacagagaa accctgtctc gaaaaaaaaa accaaaaaaa caaaaaaaaa 16680
aaaaaaaaaa aaaaaaaaaa gccaacaaca attcctggat ttgtgaattg aatatttcta 16740
gtaaagcgat agtgaactgg gagtagtggc tcacgcccgt catcctagtg cttatgaggt 16800
agagcagaaa gatcagaagt acaagaccat cctcagctac atagcaggtt caaggccagt 16860
ctagatgcat gagaccgtat ttctaaaggc taaaatgctt tttaaaggta atattagaaa 16920
cagaatagga tagggcagag tttcatgcct ggttccatgt ctgagtggtg gcaggtcaac 16980
actccagggt cactgccacc tggatcaaca ctacgaggcg cacacacagg gtctcctgcc 17040
cctatgggag atgggcggat acatggagag actaaggtcc aaaaaatggg aagatttggc 17100
agttggcctg accccctcac ctgcgtgtct gttctcacag gttggcctgc ttgggcggct 17160
gccctgcctg acccacagcc atctgtcagt ccatctgtcc gccttgaccc caggagaccc 17220
agagatcgag gaaaggatcg gagcatggtg tagacaccct cagccagccc agggagcccg 17280
gccccgcaca tctgagggaa ggaagtggct ggccaggtga gtggtctcga gacctctact 17340
cctctattcg gtttggggac aatggcaggc agtggggaca ggtgcatctc agggagcagg 17400
gagagcctct ctggggaagt ggcatccagg tagaagccag aaggtgctct ctgccacatg 17460
gtggtcagca gtcagagtga ccggtgcagg cagagaccca gcatctgtgg gcgcctgatg 17520
gagatagaac ccaggactgt gaacacgcca gaccatgtgc tgacctctga cctctgtctc 17580
agcttctatt tgttaccctt tttatgtgag ataggacttt gcttttatag ctctggcaat 17640
ctgcctgcct ctacttcctg actgctgggc ttaaagcctt gtacccacac ctctggtttt 17700
tgtttttttt gttttaatgt gtgcattctt tgtatgtgtg ggtcacaacc tgggtcagca 17760
ccgtgatccc tttgtattga gtggatatca ggatgagata ccatatggat ccgcactgtc 17820
tgtctgtctg tctgttcaat cctctggtag ctgtcacctt ctatctctgg tgagcacgct 17880
actgggatgt tccagtagtg tgtgaggccg cgctggaggg atgctttgtg ggttctttgc 17940
gcatagagta tcttgtcttt gtttcatggg aggaagcctg agtgacggtg attctgggct 18000
ggcactgtct ctctgtgtgt ctgtctgtct gtctgtctct ctctctctgt ctctctctct 18060
ctcgctgagg caagccaaaa ctatcacagg tcaagctggg ggcacccaca gtctgctgag 18120
ggggtggata gtcgggacaa agctggggga ggggagctca tgtggctgga ggccacatgg 18180
aggagctcag ccttaaagaa taggaagtca ggctggagag atggctcagc ggttaagagc 18240
actgactgtt cttccagagg tcctgagttc aattcccagc aactacatgg tggctcacaa 18300
ccatctgtaa tgggatctga tgctgtcttc tgctgtgtct gaagacagtg acagaagggt 18360
gaaggtggag agagctaggg gccggagcaa tggctcagcc gttaagagct cttgttccta 18420
cagaggacct tagtgtcagt ccagcatgcc cgtggtggca agcagctttc tgtgacttca 18480
gttcagggat ctgttgccct cttctaccct ccataggcac caggcatacc tactgtgcac 18540
taataatgtt catgtgcagt caccaggcat gcacacagag tacatacaca catgcagacg 18600
agctggacat agcctccgtg tggtggccca ggcaccaccc actggcactt tgctggtcat 18660
tgactcgtga gcttcccaga gctgcaggga gagaaacaga cagcacatgc ctgggagaca 18720
tcagaaggga gtggggctca gtggggttca gtggctcgag cagggaaagg tggccttctc 18780
tttacaggac tgtctgtcca gatccaccga aatggcccac cgccttgctc ttcccagcct 18840
cccacttcta gatctttgtc ttaacacgcc tcacagcatg atcaacagta gacaagacag 18900
cctgtgtgcc catccatcag gaatggagtc ttggtgtgtt ccatttagtg aggcctttcc 18960
tgtcaaaggc aaagacgcca gtctgtgtgt cctcaaggga aagacgccca gaccagacca 19020
gagaacctca gctgttttaa aaaacctgtg ctgtttccag gagagagcgg ccgccctgag 19080
ggatgctcaa tgtctgcttt gccacactca gtctttttgt ttagtgactg ggatatggct 19140
gatttggggg agcgcttacc ttgcaggcat gaagccctat gcttgatttc cagcaccaca 19200
ttcacagctg taatcccaga ggcaggagaa tgaggaattc aaggtccccc ttagatacag 19260
caggttcaag gccagcctga gacggaagga gaaaatgaga aatcccaggc tagtggtagt 19320
ttctgttatc tttctcgttc cttcgcttct ttctaacaga tgtagcccag gctggtccag 19380
actgtcctca aactcacaat cttctgtcct tggtcttcca agtactggga tcagaggctt 19440
gtacacagag gcctgttatg ttgctaggct agccttgaac cccaccccac ctccggaacc 19500
aaacagccct ccctccctca gcctcctgag cagctgggat cacaggtgca caccactaga 19560
agtggcttcc gcttaactcc aaggagggtc taggcacact tatgggacag aggacctgca 19620
tggtgggttt ctcttccctc tgggaattag actgagctac cacttcctgt gcataactct 19680
aggcctgctt ccccaggaaa tgcacctgcc ctgcagggtt gatcgctggt cacagcagct 19740
gatgcctgcc cagcaacacc aagagcactt tattggcagt agtgtgtctg gttgtccctt 19800
gagcctctcc cccagcacca aggaagggcc ctttgtctgt gcccaacacc ctggccactg 19860
acttgctccg accacaccca cttctttctg ctcctttggt ggttcggttc tcaccgaagc 19920
agagagaccg accaccaagg gactaaggca aaagtcaagg tcttcctcac cccggcgagt 19980
ctgagatgta aatcaaagtc agaaatagac cccaagatcc tcccccctca ccccaccccc 20040
cccacccccc caacccccca gcccccccac ccccacccag gtgtggtcta gccacatctc 20100
tctggagctg ggcctgagac cacacggggc aggctggtgc cggtgccggt gccaagtggc 20160
cttccctagt gccaaggtct ccatcccctc aggtcctgcg gcccctctgg atgcccgtgc 20220
tggcctctcc tctagcatcg tgcccaccat ggcctcagct gacaagaatg gcagcaacct 20280
cccatctgtg tctggtagcc gcctgcagag ccggaagcca cccaacctct ccatcaccat 20340
cccgccacca gagagccagg cccccggcga gcaggatagc atgcttcctg aggtgagggg 20400
ctgcccgcca caggccacag atgtgactgc ccacacagca actagacaca ctcttccatc 20460
tcagtctact gacagtcctg cagcctcaac atacgcctga aagattgcag ggagcaaggc 20520
tctgaactct gaacttggga gttctgttgc ctggtgacca agggacaagg aacactgtcc 20580
ctgagaaaag gccttgttgg gaagcctggg ctctggctgt ttacagttcc cctccctggc 20640
cctgctgtgg gctgtctgtg gaggcctgag tgggcatggg gtcccacagt gccagcagcc 20700
acccctacag cgccttgttc ttggggggat gggtcattgt ttacgtccat ctgggactct 20760
tgccccataa agagctcatt gaaaacaggc cccaaatagc gtgggctttg aacacagcct 20820
gaaacataaa ggggagctat gttggggcca cccgctcacc ctgagagtac tctaagacac 20880
gtgagaagag gcaggacatc ctggtatatg ggcatatcat gggtagggag tgtttgcact 20940
gaggtttgta cagtggaaaa cttgtgtttt gtttgttgag acagggtctc gtgtagccca 21000
ggttagcctc gaacttgctc tatagtcaac aagtactttg aactgctggt ccttcttgct 21060
ctacttcctg ggtagaaagg tgctgagtgg caagtgttca ccgccgcacc ggggggcggt 21120
gtgtagcgct gggacaggaa cccagggctt taggcgtgct gggcacactg ccaacctgag 21180
ctgtatcccc agaccttgct agaaaatgct cactttgggt tcagaatgag ggcctatgga 21240
ggactgagtg cagccagcag gctagcgtgt taaagggtct gggctatgtc ctcaactctg 21300
caataaaaag ggctgaatgg gagcccaaaa gcagccaaca ggtgagtggc ctagacactc 21360
attcatgtcc tccttgcctc cccacagagg cgcaagaacc cagcctacct gaagagtgtc 21420
agcctacagg agccccgggg acgatggcag gagggcgcag agaagcgccc cggcttccgc 21480
cgccaggcct ccctgtccca gagcatccgc aagtgagcac ctgagccctg cctggtcacc 21540
ccagcggcct ggcctttccc ggggcctgag ccctgtgtcc ccctttccag aggtgtagac 21600
aatcagggag tagcatctcc ccgtggatgt ggaaggccag aatctgaagt gatggtgtta 21660
atgggatgag aaggggctgg ggctgggcct gtgcacctga caggaagttc cacagcacgc 21720
tgcagagggg ctctccagcc ttcccagtcc cacccatcat ggggtagcct tcactctcag 21780
cctggtcgct gggctgtagc tgggaactca ggggggtgta gggaagactc actgattccc 21840
tagggccttg aagatacatg gcagggtcca tggtccattg gttaccctgt atacacacag 21900
gaacacacat gccttaccct caagtcccct ctccccacac acaccgccat cccctagacc 21960
accttccata aacacgagca ccatggcctc ccgtcacctc atacccgtgt gcctcgtgta 22020
cccgcaactc acacatcacc ctcccaacac acacacatgt accgccatcc ccctgcctcc 22080
tcctttaaca catgtacctt cgccctcacc tcctcgtgca cacgcgtgca ccaggacagg 22140
tgcgtgcaca ggtttctgcc cacaccgtat ctgttctgca ggagcacagc ccagtggttt 22200
ggggtcagcg gcgactggga gggcaagcga caaaactggc atcgtcgcag cctgcaccac 22260
tgcagcgtgc actatggccg cctcaaggcc tcgtgccaga gagaactgga gctgcccagc 22320
caggaggtgc catccttcca gggcactgag tctccaaaac cgtgcaagat gcccaaggtg 22380
ggccccctgg aggtgatggg cagcaagcgg ctctcccagg gtctgggcaa cattgttcac 22440
ccacatctct tgcagattgt ggatccactg gctcggggta gggccttccg ccatccagat 22500
gaggtggacc ggcctcacgc tgcccaccca cctctgactc caggggtcct gtctctcaca 22560
tccttcacca gtgtccgctc tggctactcc catctgcccc gccgcaagag gatatctgtt 22620
gcccatatga gctttcaggc agccgccgcc ctcctcaagg taaggtctgc attgaaggat 22680
gtatgtcccc gtccagggta gccactccac tcacctacat gtctaccctc tgtgtcagag 22740
tagtgaatgc atgcacaccc taaaggccag aacttatgtc cttcaggccc acagttcccc 22800
tgtgagccct cagcgcctcc tctgctatgg gttatgggag aagtggtggg ggggggggag 22860
gtattggatg tagatgcctt gagtgccggg tgccaactgt tcccgttagc aggcaagagc 22920
tcgtgaggga agagctgaga gctgatcctg attactggaa ggagaggctg tgtagggccg 22980
gctgcagcca gagccccatc ctggcctgct ctgagtactt ccttcagccc gtctacttat 23040
ccaatgtcct gtgcctttgc caacctggtc ctggggttct gagccctcct tgacgcttct 23100
gttccatgcc caggggcgtt ccgtgctaga tgcgactggg cagcggtgcc ggcatgtcaa 23160
acgcagcttc gcttacccca gcttcctgga ggaggatgct gtcgatggag ctgacacctt 23220
cgactcctcc ttttttagta aggcaagcat ggggtgtgga ctctgggcgg gggatggggt 23280
ggcctgagag ctaggaggag tgaccttggc cttgactgtg gcttgtggga tcccaggaag 23340
gtccagaggc agggtggggt atggcctttg tgagccattg gtctgggctc ccttagaagg 23400
gggtgtggag tggagcacga acccgctggg aaagttagga gtgacaagca tgcggctgcc 23460
cttccatcct gaagagactg tatagctttg ccttgccctt gattggagtg ctacgatggt 23520
ccttggggca gtggctcctc acactgtcct tggtgtccct ctactccagg aagaaatgag 23580
ctccatgcct gacgatgtct ttgagtcccc cccactctct gccagctact tccgaggtgt 23640
cccacactct gcctccccgg tctccccgga tggagtgcac atcccgctgt gagtacaggg 23700
tgggactctc cagcccctgc tgagccctgg cagggtcctc aagctaagag cctctgtcat 23760
caccagaaaa gaatacagcg gtggccgagc cctgggtccc gggacccagc gtggcaaacg 23820
cattgcctcc aaagtaaagc actttgcatt tgaccggaag aagaggcact acggcctggg 23880
cgtcgtgggt aactggctca accgaagcta tcgacgcagc atcagcagca ccgtgcagcg 23940
gcagctggag agcttcgata gccaccggtg agcccccagg agccagtctg agcagaggac 24000
taagtggcta gagtttccaa acctctcagg cctcttcatc ccaaacatgg ccccttctca 24060
gtcagtaagc attctgagag cgcctcctgc aggtcctgca ggtaatgaca agctcctggg 24120
cacacacatg ctcagggagc gctctgtagc ctggagagag ccagctgaca ctgctacctt 24180
atcctcaaca tggcccccag acagcagtca gtcagtcagt cagtcagtca gtcaacaaac 24240
acagatcaag gacaactata gcagtctctg gacacagccc agagagaggg gcattgcgcc 24300
tggacaggtg ccctggggct ggcaaggcgg ttcagtgagg ctagggatga gtttgatccc 24360
tggaaccaat aaaaagaaag gagagaagcg actccacaga gttgtcgcct gacgtccaca 24420
tgcctgcgag tcatgttggg gacacacaca cacacaactc taataatttt aaaatgatct 24480
tttaagccca gcatgctggc acatgctttt agttccagta ttcaggaggc agaggcagac 24540
agaggtctat gagttcaaag ctagcccggt ctaaatagtg actactagct aatgctccat 24600
agagaaacgt tctctcaaag ccaaaaggcg gttaaaagag aacaaaggga gttggcgcct 24660
ggagtgaggg gtcctggggg gagtggacac agagatgttc agggaaactg gagattaaag 24720
agtgatagcc aaagtgtggt tgacagtgtg acctgatagg cctcggactc caaattacac 24780
aaagtaagaa agggcaggag tcgaagtaag aaagggcagg agtggtggag tgggtgggga 24840
gcgggtgggg gacttttggg atagcattgg aaatgtaaat gaaataaata cctaataaat 24900
aaagtaaaga aaaagaaagg gcaggagtgg tgggcaagcg gctagggtgg aggggtgctg 24960
ttagggtggg atgccgtgag cagaggtgtg ggccccccca ggtgatgtga agtgtgcaca 25020
aaggtcctgg ggcttcaggg gccgtggcct ggtccaggaa gcacaagcag aggaggtgag 25080
cagcaattgc aggtgagcac aggcaggctt gccagttatc agcaggggat ggctttgatc 25140
ttcacacagt aggcagtggg aagccatcgt gggctttgaa ctgagagaga cactggggat 25200
gcaccttcca agtttctgtg gggaaggctg agctggggga atgcctgcca tgcccaggtg 25260
aagggcgtga ggagcggggc atgagctctg ccaggctgac tggaagcctc ccccggcagg 25320
ccctacttca cctactggct gacgttcgtt cacatcatca tcaccttgct ggtgatctgc 25380
acctatggca tcgcacctgt gggctttgcc cagcacgtta ccacccagct ggtgagtagg 25440
gttcctcctg gggggtcccc ggcctctccc aaggagcttt ggcacagttg gcaccaagta 25500
tctcccacca cagtaccctg gcccaagttg gagatgcctg aggctcatag cctctttcta 25560
gaggcccttt tctggggatg cccccacccc cgtccctttc tcttctcacg ccgagggctc 25620
tggctcctct aatgccacaa actaccttct tgataggtgc tgaagaacag aggcgtgtat 25680
gagagcgtga agtacatcca gcaggagaac ttctggattg gccccagctc ggtgaggccc 25740
aggatgcccg ggagccctgt atcctgccac tccacactgg gcagaggggt ggatggtagg 25800
gtgccccgcc cactgcttcc gagtatgggg cactggctca cagtcccccc cccccccact 25860
ccagattgac ctcattcacc tgggagcaaa gttctcgccc tgcatccgga aggaccagca 25920
aattgagcag ctggtacgga gggagcgcga cattgagcgc acctctggct gctgtgtcca 25980
gaatgaccgc tcgggctgca tccagaccct gaagaaggac tgctcggtgg gtcctgcccc 26040
tacccctgca cctgcccctg cccctgccag cctccttcct tccccggccc aaagctgggc 26100
ttggaaagct ggacagtagt tcctaggaag tacccaagtc ctggggaaat gggaaaagcc 26160
cttgtcctgc ggggttcgct gcccacacca tctgactgac acggcctgac cacctgtcca 26220
ccctctagga gactttagcc acgttcgtaa agtggcagaa tgatactggg ccctcagaca 26280
agtctgacct gagccagaag cagccatcgg cggttgtgtg ccaccaagac cccaggtaca 26340
gccaagagcc tcctatgggt ccagagtggc acccagctgt tggagctgcc atctgtgatg 26400
ctggtgggtg ggtgtggcag gctgggacat cccagccttt tattttgctc aatctgaccc 26460
ctgcttctag gacctgtgaa gagcctgcct ccagtggggc ccacatctgg cctgatgaca 26520
ttaccaagtg gccggtgagt aggagatcca tggagaaagg tctgggatga gggtggggac 26580
agctggcttt ccgtcatgag gcccactgcc attggtcccc tgtctcttag atctgcacag 26640
agcaggctca gagcaaccac acgggcttgt tgcacataga ctgtaagatc aaaggccgcc 26700
cctgctgcat cggcaccaag ggcaggtgag ccggtgcctc caaccaaccc ctgcaggctg 26760
atggacctct gtgactgtct tctgttctct gctcttgggt gatgggggga ggcagggatt 26820
gaggggcagt gatatagaaa ggagcttgtc ccatcctgcc tgccatgccc agggactggg 26880
ctccccagct gatgctcttt agaacgctga cagccgtctg cttcctgtcc acagctgcga 26940
gatcaccact cgggagtact gtgagttcat gcatggctat ttccatgaag acgcgacgct 27000
gtgttcccag gtagtggaag ctgtagggat tctgagggcc actggggtcc ttaccctttg 27060
gaagcctcag acttggcttg cctcccaggg cagaactact gaccctgtgt ctcccaccca 27120
ggtgcactgt ttagacaagg tgtgtgggct cctgcctttc ctcaaccctg aggtccctga 27180
ccagttctac cggatctggc tgtctttatt cctgcatgct gggtaagagg caccctgttg 27240
ccccatgctc agactcccat gtctcccctc ttgggtgccg gagaaaaggg cttccagacc 27300
gagcacactg gctcaacctg ctagtgctag actgcgctgt ggtgtgctct gcgggtgacc 27360
atgggcacac aggaaaggct gatggtgctc atgtgcctac cccagcatag tgcactgcct 27420
tgtgtctgtg gtcttccaaa tgaccatcct gagggaccta gagaagctgg ccggctggca 27480
ccgcatctcc atcatcttca tccttagtgg cattacaggc aacctggcca gcgccatctt 27540
cctcccctac cgggcagagg tacaaacttg ggagacaagg gcagagaggg tgggatgagc 27600
ccttcctttt ggatctaaag ctttataaca tatggggagg accattgtag cctgtgggga 27660
ggaccattgt ggcttgtcag gaggactatt gtggcctgtg gggaggatca ctgtggccta 27720
tgggaaggac caaacctgct gcttcttgct ctggttccac cccagaatct gcaacaaggg 27780
cagagtccct gttgtgtcaa gcttacctat agatgggcag ctaaggtaga acctattgat 27840
tagcctctta attcatgaca ggagggaaca gagatactct tgagtcccca gagatccttg 27900
ctccttgttc tgtgaaaccc tacatttggc tcctctccac cctcaggagg agaggtcttg 27960
agtctgttgc tccttctggc ctgcgatctc tccactgcct gtagtctcct aggacaggct 28020
ggcttgtgct aagcacgggg ttagagcaca cccaggtttg ctgcagggtt ggacagagca 28080
gggccagcag ctcctgtggc atcctccgag tgggagatgt gccccacagc tggtacctgg 28140
cacccagcat cagtggcgac atctctcctc cctgacccca ggtgggccca gccgggtcgc 28200
agttcggcct cctcgcctgc ctcttcgtgg agctgttcca gagctggcag ctgttggagc 28260
ggccgtggaa ggccttcttc aacctgtcgg ccattgtgct tttcctcttc atctgtggcc 28320
tcctgccctg gatagacaac atcgcccaca tcttcgggtt cctcagcggc atgcttctgg 28380
ccttcgcctt cctgccttac attaccttcg gcaccagcga caagtaccgc aagcgagccc 28440
tcatcctcgt gtcgctgctg gtctttgctg ggctctttgc ttccctggtg ctgtggctgt 28500
acatctaccc catcaactgg ccctggatcg agtacctcac ctgctttccc ttcaccagcc 28560
gcttctgtga gaagtacgag ctagaccagg tgctacacta actgcagaga ttgtgtgtct 28620
gccctgggcc gtgtgtctat gaaccggtgg ggccctgagc ccagcagctc ggtccacact 28680
caaggctgac tccagatgag acgggcggta aaggcaggct ccccagggag atgactcctc 28740
ctttctcagg tctgaatgtt cctgacccaa gtctggggga catccaggac acttgcttct 28800
ctgaggctca ggtcccaggc cctgcctgcc tctctggctc tataaagatg ataacttttc 28860
ttgggcctct ggcctctgcg ggtgctgtct ccccactgac actgtgactg tgacctcgcc 28920
agacacacag ctgctctctc agttgtcccc agggttgagg tccttaccat gctgctatga 28980
ccccgttttc ctgtttctcc tctcctccct gtccttcctg tgtttgtccg tggactcgtg 29040
agcctgctcc tgaggctcct ggacatagag cattgtgggg aaggctctgg ctgttgtcta 29100
tgggggatga caagcaagga gagatggcta tacagggatg ctaggggctt ttgttaagca 29160
aagaagccag ctctcctaag cccatcagct gccctagctc cagcatgtgt ctggctgcac 29220
aggttggctc tgatcccagg atgcccctgc cacctgccct cactcctgcg tggccgtggg 29280
ccgagccgcc ttgaggacta gctcccagag gaggcctgag gcccagactg gtgggttttt 29340
tggttttgtt ttgttttttt ttttccaatt tatattatgg tcctaatttt gtaaagtaac 29400
gctaactttg tacggatgat gtctcaagtt tattaaatga cattctttat taaaatgctg 29460
ccttttgcct tagacctcca agagaaggaa agctagaact tggggctaca gagatggctc 29520
acttcctata gagaacctgg gttcagttca gagatccgcc tgcctctgcc tcccaagtac 29580
tgggattaaa ggtgtgcgct accaccgccc cagccaaaac aatgttttta tttgaaagag 29640
aaagccccgg ggccttgagg ctgaagcaga ccggaacact tgggatctct gtcatttagt 29700
tgaactagaa accagattga gatctcagca gagcccccaa ggaccctgag agaactgggt 29760
tacgtgtaga gccctgagac ctcaacccca gctgctctgc ctttgctcca gggacatcag 29820
gggctgatgg gcagcaggag tggcctgttc cagcagaggt ggaccagcgg ggaggaggcc 29880
acgtgtttgc tccagtcagc tcgaagaaga ccctacacac acccatgagg cacagccact 29940
ggggacatag ctactttatt cgtgggcaga ggtgccagtc ctgtggctgg tgggggaacc 30000
agggaggcag gggggtgggc cggcacattg gtggctgact gcagtttggt gtggc 30055
<210> 3
<211> 856
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 3
Met Ser Glu Ala Arg Arg Asp Ser Thr Ser Ser Leu Gln Arg Lys Lys
1 5 10 15
Pro Pro Trp Leu Lys Leu Asp Ile Pro Ala Ala Val Pro Pro Ala Ala
20 25 30
Glu Glu Pro Ser Phe Leu Gln Pro Leu Arg Arg Gln Ala Phe Leu Arg
35 40 45
Ser Val Ser Met Pro Ala Glu Thr Ala Arg Val Pro Ser Pro His His
50 55 60
Glu Pro Arg Arg Leu Val Leu Gln Arg Gln Thr Ser Ile Thr Gln Thr
65 70 75 80
Ile Arg Arg Gly Thr Ala Asp Trp Phe Gly Val Ser Lys Asp Ser Asp
85 90 95
Ser Thr Gln Lys Trp Gln Arg Lys Ser Ile Arg His Cys Ser Gln Arg
100 105 110
Tyr Gly Lys Leu Lys Pro Gln Val Ile Arg Glu Leu Asp Leu Pro Ser
115 120 125
Gln Asp Asn Val Ser Leu Thr Ser Thr Glu Thr Pro Pro Pro Leu Tyr
130 135 140
Val Gly Pro Cys Gln Leu Gly Met Gln Lys Ile Ile Asp Pro Leu Ala
145 150 155 160
Arg Gly Arg Ala Phe Arg Met Ala Asp Asp Thr Ala Asp Gly Leu Ser
165 170 175
Ala Pro His Thr Pro Val Thr Pro Gly Ala Ala Ser Leu Cys Ser Phe
180 185 190
Ser Ser Ser Arg Ser Gly Phe Asn Arg Leu Pro Arg Arg Arg Lys Arg
195 200 205
Glu Ser Val Ala Lys Met Ser Phe Arg Ala Ala Ala Ala Leu Val Lys
210 215 220
Gly Arg Ser Ile Arg Asp Gly Thr Leu Arg Arg Gly Gln Arg Arg Ser
225 230 235 240
Phe Thr Pro Ala Ser Phe Leu Glu Glu Asp Met Val Asp Phe Pro Asp
245 250 255
Glu Leu Asp Thr Ser Phe Phe Ala Arg Glu Gly Val Leu His Glu Glu
260 265 270
Met Ser Thr Tyr Pro Asp Glu Val Phe Glu Ser Pro Ser Glu Ala Ala
275 280 285
Leu Lys Asp Trp Glu Lys Ala Pro Asp Gln Ala Asp Leu Thr Gly Gly
290 295 300
Ala Leu Asp Arg Ser Glu Leu Glu Arg Ser His Leu Met Leu Pro Leu
305 310 315 320
Glu Arg Gly Trp Arg Lys Gln Lys Glu Gly Gly Pro Leu Ala Pro Gln
325 330 335
Pro Lys Val Arg Leu Arg Gln Glu Val Val Ser Ala Ala Gly Pro Arg
340 345 350
Arg Gly Gln Arg Ile Ala Val Pro Val Arg Lys Leu Phe Ala Arg Glu
355 360 365
Lys Arg Pro Tyr Gly Leu Gly Met Val Gly Arg Leu Thr Asn Arg Thr
370 375 380
Tyr Arg Lys Arg Ile Asp Ser Tyr Val Lys Arg Gln Ile Glu Asp Met
385 390 395 400
Asp Asp His Arg Pro Phe Phe Thr Tyr Trp Leu Thr Phe Val His Ser
405 410 415
Leu Val Thr Ile Leu Ala Val Cys Ile Tyr Gly Ile Ala Pro Val Gly
420 425 430
Phe Ser Gln His Glu Thr Val Asp Ser Val Leu Arg Lys Arg Gly Val
435 440 445
Tyr Glu Asn Val Lys Tyr Val Gln Gln Glu Asn Phe Trp Ile Gly Pro
450 455 460
Ser Ser Glu Ala Leu Ile His Leu Gly Ala Lys Phe Ser Pro Cys Met
465 470 475 480
Arg Gln Asp Pro Gln Val His Ser Phe Ile Leu Ala Ala Arg Glu Arg
485 490 495
Glu Lys His Ser Ala Cys Cys Val Arg Asn Asp Arg Ser Gly Cys Val
500 505 510
Gln Thr Ser Lys Glu Glu Cys Ser Ser Thr Leu Ala Val Trp Val Lys
515 520 525
Trp Pro Val His Pro Ser Ala Pro Asp Leu Ala Gly Asn Lys Arg Gln
530 535 540
Phe Gly Ser Val Cys His Gln Asp Pro Arg Val Cys Asp Glu Pro Ser
545 550 555 560
Ser Glu Asp Pro His Glu Trp Pro Glu Asp Ile Thr Lys Trp Pro Ile
565 570 575
Cys Thr Lys Ser Ser Ala Gly Asn His Thr Asn His Pro His Met Asp
580 585 590
Cys Val Ile Thr Gly Arg Pro Cys Cys Ile Gly Thr Lys Gly Arg Cys
595 600 605
Glu Ile Thr Ser Arg Glu Tyr Cys Asp Phe Met Arg Gly Tyr Phe His
610 615 620
Glu Glu Ala Thr Leu Cys Ser Gln Val His Cys Met Asp Asp Val Cys
625 630 635 640
Gly Leu Leu Pro Phe Leu Asn Pro Glu Val Pro Asp Gln Phe Tyr Arg
645 650 655
Leu Trp Leu Ser Leu Phe Leu His Ala Gly Ile Leu His Cys Leu Val
660 665 670
Ser Val Cys Phe Gln Met Thr Val Leu Arg Asp Leu Glu Lys Leu Ala
675 680 685
Gly Trp His Arg Ile Ala Ile Ile Tyr Leu Leu Ser Gly Ile Thr Gly
690 695 700
Asn Leu Ala Ser Ala Ile Phe Leu Pro Tyr Arg Ala Glu Val Gly Pro
705 710 715 720
Ala Gly Ser Gln Phe Gly Ile Leu Ala Cys Leu Phe Val Glu Leu Phe
725 730 735
Gln Ser Trp Gln Ile Leu Ala Arg Pro Trp Arg Ala Phe Phe Lys Leu
740 745 750
Leu Ala Val Val Leu Phe Leu Phe Ala Phe Gly Leu Leu Pro Trp Ile
755 760 765
Asp Asn Phe Ala His Ile Ser Gly Phe Val Ser Gly Leu Phe Leu Ser
770 775 780
Phe Ala Phe Leu Pro Tyr Ile Ser Phe Gly Lys Phe Asp Leu Tyr Arg
785 790 795 800
Lys Arg Cys Gln Ile Ile Ile Phe Gln Val Val Phe Leu Gly Leu Leu
805 810 815
Ala Gly Leu Val Val Leu Phe Tyr Phe Tyr Pro Val Arg Cys Glu Trp
820 825 830
Cys Glu Phe Leu Thr Cys Ile Pro Phe Thr Asp Lys Phe Cys Glu Lys
835 840 845
Tyr Glu Leu Asp Ala Gln Leu His
850 855
<210> 4
<211> 199
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
cgtgcaagat gcccaaggtg ggccccctgg aggtgatggg cagcaagcgg ctctcccagg 60
gtctgggcaa cattgttcac ccacatctct tgcagattgt ggatctactg gctcggggta 120
gggccttccg ccatccagat gaggtggacc ggcctcacgc tgcccaccca cctctgactc 180
caggggtcct gtctctcac 199
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Pro Lys Lys Lys Arg Lys Val
1 5
<210> 6
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys
1 5 10
<210> 7
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
gcagattgtg gatccac 17
<210> 8
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
acacacacat gtaccgccat 20
<210> 9
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
ttctggcctt tagggtgtgc 20
Claims (15)
1.一种经遗传修饰的NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG)小鼠,其中所述小鼠的基因组包含突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长。
2.权利要求1的经遗传修饰的NSG小鼠,其还包含异种肿瘤细胞。
3.权利要求2的经遗传修饰的NSG小鼠,其中所述异种肿瘤细胞是获自人类受试者的肿瘤。
4.权利要求2或3的经遗传修饰的NSG小鼠,其中所述异种肿瘤细胞是获自人类受试者的乳腺肿瘤的肿瘤细胞。
5.权利要求1-4中任一项的经遗传修饰的NSG小鼠,其中所述小鼠是NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠。
6.一种产生用于评估异种肿瘤细胞的小鼠模型系统的方法,所述方法包括:
提供经遗传修饰的NSG小鼠,其中所述小鼠的基因组包括突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于iRhom2的N-末端区域中的一个或多个选自p.I156T、p.D158N和p.P159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长;
提供异种肿瘤细胞;和
将所述异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,由此产生用于评估异种肿瘤细胞的小鼠模型系统。
7.权利要求6的方法,其中所述异种肿瘤细胞是获自人类受试者的肿瘤。
8.权利要求6或7的方法,其中所述异种肿瘤细胞是获自人类受试者的乳腺肿瘤的肿瘤细胞。
9.权利要求5-8中任一项的方法,其中所述小鼠是NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠。
10.一种鉴定测试化合物的抗肿瘤活性的方法,所述方法包括:
提供经遗传修饰的NSG小鼠,其中所述小鼠的基因组包含突变的Rhbdf2基因,以使得所述小鼠表达突变的iRhom2蛋白——其由于的N-末端区域中的一个或多个选自p.I156T、p.D158N和pP 159L的突变而与野生型小鼠iRhom2蛋白不同,其中与表达野生型iRhom2蛋白的相同遗传背景的小鼠相比,所述经遗传修饰的NSG小鼠的特征在于无毛表型和增加的异种肿瘤生长;
提供异种肿瘤细胞;
将所述异种肿瘤细胞给予至所述经遗传修饰的NSG小鼠,产生了包括异种肿瘤细胞的经遗传修饰的NSG小鼠;
将测试物质给予至所述包括异种肿瘤细胞的经遗传修饰的NSG小鼠;
在将所述测试物质给予至所述包含异种肿瘤细胞的经遗传修饰的NSG小鼠后,测定所述异种肿瘤细胞对所述测试物质的反应;以及
将所述反应与标准进行比较以确定所述测试物质对所述异种肿瘤细胞的作用,其中所述测试物质对所述异种肿瘤细胞的抑制作用将所述测试物质鉴定为具有抗肿瘤活性。
11.权利要求10的方法,其中所述异种肿瘤细胞是获自人类受试者的肿瘤。
12.权利要求10或11的方法,其中所述异种肿瘤细胞是获自人类受试者的乳腺肿瘤的肿瘤细胞。
13.权利要求10-12中任一项的方法,其中所述小鼠是NOD.Cg-PrkdcscidIl2rgtm1WjlRhbdfP159L/SzJ小鼠。
14.权利要求10-13中任一项的方法,其中所述测试物质是抗体。
15.权利要求10-14中任一项的方法,其中所述测试物质是抗癌剂。
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US62/248,417 | 2015-10-30 | ||
PCT/US2016/059711 WO2017075585A1 (en) | 2015-10-30 | 2016-10-31 | Compositions and methods relating to tumor analysis |
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Cited By (2)
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CN114480408A (zh) * | 2022-02-17 | 2022-05-13 | 南开大学 | Rhx6基因以及其在制备抗乳腺癌药物中的应用 |
CN116120398A (zh) * | 2023-02-23 | 2023-05-16 | 南开大学 | 多肽kwqrksirh、制备方法及其在增敏致dna损伤类肿瘤疗法中的应用 |
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WO2023114461A1 (en) * | 2021-12-17 | 2023-06-22 | The Jackson Laboratory | Humanized mouse model of fibrosis |
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CN114480408B (zh) * | 2022-02-17 | 2023-12-19 | 南开大学 | Rhx6基因以及其在制备抗乳腺癌药物中的应用 |
CN116120398A (zh) * | 2023-02-23 | 2023-05-16 | 南开大学 | 多肽kwqrksirh、制备方法及其在增敏致dna损伤类肿瘤疗法中的应用 |
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US20180325085A1 (en) | 2018-11-15 |
WO2017075585A1 (en) | 2017-05-04 |
AU2016343860A1 (en) | 2018-05-10 |
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