CN114231489A - 用于重编程的功能性片段、组合及其应用 - Google Patents
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Abstract
用于重编程的功能性片段、组合及其应用。本发明提供了一组可协同促进胶质细胞转分化,重编程为有功能的神经元或类神经元的转录因子、转录因子组合,通过在体内或体外促进这组转录因子的表达,可有效地应用在胶质细胞转分化修复神经系统损伤或利用关键转录因子转分化能力来限制胶质细胞来源的脑肿瘤恶化,以及所发现的转录因子及其组合在制备神经系统疾病药物中的应用。
Description
技术领域
本发明属于生物技术和基因治疗领域,具体地,本发明涉及将胶质细胞来源的细胞转分化为神经元的 方法,以及应用这一方法实现神经系统损伤修复或治疗胶质细胞来源肿瘤的方法。
背景技术
哺乳动物的中枢神经系统损伤和多种神经退行性疾病引起的主要病理变化是不可逆的神经元变性坏 死和神经环路破坏。如何补充替代损伤和疾病的大脑或脊髓中死亡丢失的神经元并重建神经环路是治疗的 关键步骤。由于成年哺乳动物的中枢神经系统(大脑和脊髓)自我修复的能力非常有限,很难靠自身来弥 补神经元细胞的丢失。
由于外源性神经元或神经源性细胞的移植的效率较低,而且有致瘤性和免疫原性的潜在风险。近年来, 细胞重编程技术的出现给再生医学带来了革命性的变化。通过表达单个或组合的多个神经原性转录因子实 现体内重编程星形胶质细胞诱导产生神经元有望成为神经元替代疗法的重要新策略。
神经胶质瘤简称胶质瘤,也称为胶质细胞瘤,广义是指所有神经上皮来源的肿瘤,狭义是指源于各 类胶质细胞的肿瘤。胶质瘤是致死率最高的恶性肿瘤之一,也是最常见的原发性中枢神经系统肿瘤,占脑 和中枢神经系统肿瘤的30%、占脑恶性脑肿瘤的80%,是人类健康的严重威胁。根据世界卫生组织 (WHO)1999年的分类方案分为星形细胞瘤、少支胶质瘤、室管膜瘤、混合性胶质瘤、脉络丛瘤、来源不 肯定的神经上皮组织瘤、神经元及神经元神经胶质混合瘤、松果体实质肿瘤、胚胎性肿瘤、神经母细胞瘤 肿瘤。胶质瘤和正常神经组织交错生长,边界不清,瘤组织不易清理干净,胶质瘤易复发。同时,由于血 脑屏障的存在,使普通的抗肿瘤药物疗效不佳。目前胶质细胞瘤的治疗仍是医学界的为满足临床需求。近 年来,有部分研究已经发现,部分神经源性转录因子或转录因子组合已经可以在体外或体内将脑胶质瘤细 胞转化为类神经元,且限制了胶质瘤细胞的增殖能力。但是,现有的转录因子或转录因子组合仅被证实用 于体外或体内转化效率偏低,难以实现实际的临床应用。
因此,寻找合适的转录因子或其组合,在体内诱导胶质细胞转分化为有活性的神经元,对于大脑和脊 髓神经系统修复非常地重要。同时,借鉴转录因子的重编程技术,应用在胶质细胞来源的脑胶质瘤,也是 目前亟待解决的一种治疗方案。
发明内容
本发明提供了一组协同促进胶质细胞转分化,重编程为有功能的神经元或类神经元的转录因子、转录 因子组合,通过在体内或体外增加这组转录因子的表达的方法,以及这组转录因子在制备神经系统疾病药 物中的应用。
本发明第一方面,提供了一组可协同促进胶质细胞转分化的功能性片段,其中,所述的功能性片段含 有至少一个促进转录因子表达的功能性片段,选自促进NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、 Ptf1a、Pax6和/或Otx2等转录因子表达的功能性片段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Ascl1转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进NeuroD1转录因子表达功能性 片段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Brn2转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Ngn2转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Gsx1转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Tbr1转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Dlx2转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Ptf1a转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Pax6转录因子表达的功能性片 段;
在另一优选例中,所述促进转录因子表达的功能性片段至少包括促进Otx2转录因子表达的功能性片 段;
在一优选例中,所述的功能性片段组合含有至少二个促进转录因子表达的功能性片段,选自促进 NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2等转录因子表达的功能性片 段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Brn2转录因子表达的功能性 片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促进 NeuroD1、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2等转录因子表达的功能性片段;更优 选地,所述的另一促进转录因子表达的功能性片段选自任一促进NeuroD1、Ascl1或Ngn2等转录因子表 达的功能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进NeuroD1转录因子表达的功 能性片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促 进Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2等转录因子表达的功能性片段;更优选 地,所述的另一促进转录因子表达的功能性片段选自任一促进Brn2、Ascl1或Ngn2等转录因子表达的功 能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Gsx1转录因子表达的 功能性片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一 促进NeuroD1、Ascl1、Ngn2、Brn2、Tbr1、Dlx2、Ptf1a、Pax6或Otx2等转录因子表达的功能性片段; 更优选地,所述的另一促进转录因子表达的功能性片段选自任一促进Ascl1、Ngn2或Tbr1等转录因子表 达的功能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Tbr1转录因子表达的功能性 片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促进 NeuroD1、Ascl1、Ngn2、Brn2、Gsx1、Dlx2、Ptf1a、Pax6或Otx2等转录因子表达的功能性片段;更优 选地,所述的另一促进转录因子表达的功能性片段选自任一促进Ascl1、Ngn2或Gsx1等转录因子表达的 功能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Dlx2转录因子表达的功能性 片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促进 NeuroD1、Ascl1、Ngn2、Brn2、Tbr1、Gsx1、Ptf1a、Pax6或Otx2等转录因子表达的功能性片段;更优 选地,所述的另一促进转录因子表达的功能性片段选自任一促进Ascl1、Ngn2或Ptf1a等转录因子表达的 功能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Ptf1a转录因子表达的功能性 片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促进 NeuroD1、Ascl1、Ngn2、Brn2、Tbr1、Gsx1、Dlx2、Pax6或Otx2等转录因子表达的功能性片段;更优选 地,所述的另一促进转录因子表达的功能性片段选自任一促进Ascl1、Ngn2或Dlx2等转录因子表达的功 能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Pax6转录因子表达的功能性 片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促进 NeuroD1、Ascl1、Ngn2、Brn2、Tbr1、Gsx1、Ptf1a、Dlx2或Otx2等转录因子表达的功能性片段;更优 选地,所述的另一促进转录因子表达的功能性片段选自任一促进Ascl1、Ngn2或Otx2等转录因子表达的 功能性片段;
在另一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Otx2转录因子表达的功能性 片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选自任一促进 NeuroD1、Ascl1、Ngn2、Brn2、Tbr1、Gsx1、Ptf1a、Dlx2或Pax6等转录因子表达的功能性片段;更优 选地,所述的另一促进转录因子表达的功能性片段选自任一促进Ascl1、Ngn2或Pax6等转录因子表达的 功能性片段;
在一优选例中,所述的促进转录因子表达的功能性片段至少包括促进Ascl1或Ngn2任一的转录因子 表达的功能性片段与另一促进转录因子表达的功能性片段,所述的另一促进转录因子表达的功能性片段选 自任一促进NeuroD1、Brn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2等转录因子表达的功能性片段;
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段至少包括促进NeuroD1与Brn2两个 转录因子表达的功能性片段、或促进Gsx1与Tbr1两个转录因子表达的功能性片段、或促进Dlx2与Ptf1a 两个转录因子表达的功能性片段、或促进Pax6与Otx2两个转录因子表达的功能性片段;
在一优选例中,所述的可协同促进胶质细胞转分化的功能性片段至少包括促进Ascl1或Ngn2任一的 转录因子表达的功能性片段与另一可协同促进胶质细胞转分化的功能性片段的组合,所述的另一可协同促 进胶质细胞转分化的功能性片段组合选自促进NeuroD1与Brn2两个转录因子表达的功能性片段组合、 或促进Gsx1与Tbr1两个转录因子表达的功能性片段组合、或促进Dlx2与Ptf1a两个转录因子表达的 功能性片段组合、或促进Pax6与Otx2两个转录因子表达的功能性片段组合;
所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段可以是编码所述转 录因子的多核苷酸,或多核苷酸转译后的功能性的蛋白、多肽,或促进转录因子表达小分子药物、大分子 药物、核酸药物,或位于所述转录因子上游调控转录因子表达上调的多核苷酸或功能性蛋白、多肽、小分 子药物或大分子药物、核酸药物等;
在一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为功 能性的NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2等转录因子的蛋白或 编码NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2等转录因子功能性蛋白 的核酸序列;优选地,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段来 源于哺乳动物,较佳地,来源于人或非人灵长类哺乳动物。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的NeuroD1蛋白,所述蛋白序列如SEQ ID NO.:1或SEQ IDNO.:2;编码所述的NeuroD1功能性 蛋白的多核苷酸序如SEQ ID NO.:3或SEQ ID NO.:4所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Brn2蛋白,所述蛋白序列如SEQ ID NO.:5或SEQ ID NO.:6;编码所述的Brn2功能性蛋白的 多核甘酸序如SEQ ID NO.:7或SEQ ID NO.:8所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Ascl1蛋白,所述蛋白序列如SEQ ID NO.:9或SEQ ID NO.:10或SEQ ID NO:41;编码所述的 Ascl1功能性蛋白的多核甘酸序如SEQ ID NO.:11或SEQID NO.:12所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Ngn2蛋白,所述蛋白序列如SEQ ID NO.:13或SEQ ID NO.:14;编码所述的Ngn2功能性蛋白 的多核甘酸序如SEQ ID NO.:15或SEQ ID NO.:16所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Gsx1蛋白,所述蛋白序列如SEQ ID NO.:17或SEQ ID NO.:18;编码所述的Gsx1功能性蛋白 的多核甘酸序如SEQ ID NO.:19或SEQ ID NO.:20所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Tbr1蛋白,所述蛋白序列如SEQ ID NO.:21或SEQ ID NO.:22;编码所述的Tbr1功能性蛋白 的多核甘酸序如SEQ ID NO.:23或SEQ ID NO.:24所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Dlx2蛋白,所述蛋白序列如SEQ ID NO.:25或SEQ ID NO.:26;编码所述的Dlx2功能性蛋白 的多核甘酸序如SEQ ID NO.:27或SEQ ID NO.:28所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Ptf1a蛋白,所述蛋白序列如SEQ ID NO.:29或SEQ ID NO.:30;编码所述的Ptf1a功能性蛋白 的多核甘酸序如SEQ ID NO.:31或SEQ ID NO.:32所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Pax6蛋白,所述蛋白序列如SEQ ID NO.:33或SEQ ID NO.:34;编码所述的Pax6功能性蛋白 的多核甘酸序如SEQ ID NO.:35或SEQ ID NO.:36所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 功能性的Otx2蛋白,所述蛋白序列如SEQ ID NO.:37或SEQ ID NO.:38;编码所述的Otx2功能性蛋白 的多核甘酸序如SEQ ID NO.:39或SEQ ID NO.:40所示。
在另一优选例中,所述可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片段为 经改造后的Ascl1功能性的蛋白,所述蛋白序列如SEQ ID NO.:41所示。
在另一优选例中,当所述的可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性 片段为功能性蛋白时,所述的功能性蛋白序列与SEQ ID NO.:1、2、5、6、9、10、13、14、17、18、21、 22、25、26、29、30、33、34、37、38和/或41的序列同源性不低于85%;更优地,所述的功能性蛋白序 列与SEQ ID NO.:1、2、5、6、9、10、13、14、17、18、21、22、25、26、29、30、33、34、37、38和 /或41序列同源性不低于95%;最优地,所述的功能性蛋白序列与SEQ ID NO.:1、2、5、6、9、10、13、 14、17、18、21、22、25、26、29、30、33、34、37、38和/或41的序列同源性不低于99%。
在另一优选例中,当所述的可协同促进胶质细胞转分化的功能性片段或促进转录因子表达的功能性片 段为编码功能性蛋白的多核苷酸时,所述的编码功能性蛋白的多核核酸序列与SEQ ID NO.:3、4、7、8、 11、12、15、16、19、20、23、24、27、28、31、32、35、36、39和/或40的序列同源性不低于75%;更 优地,所述的编码功能性蛋白的多核核酸序列与SEQ IDNO.:3、4、7、8、11、12、15、16、19、20、23、 24、27、28、31、32、35、36、39和/或40的序列同源性不低于85%;最优地,所述的编码功能性蛋白的 多核核酸序列与SEQ ID NO.:3、4、7、8、11、12、15、16、19、20、23、24、27、28、31、32、35、36、 39和/或40的序列同源性不低于95%。
所述的胶质细胞为任何来自人或非人哺乳动物的星形胶质细胞、NG2胶质细胞、少突胶质细胞、小 胶质细胞、或处于损伤状态下的胶质细胞、胶质细胞来源的肿瘤细胞等;所述的损伤状态下的胶质细胞为 组织或胶质细胞周边环境处于机械性的创伤、中风或神经退行性疾病引起的神经元死亡、凋亡从而致使神 经信号传导受阻或紊乱状态下的胶质细胞;所述胶质细胞来源的肿瘤细胞一般为胶质瘤细胞,选自来源于 人或非人哺乳动物的星形细胞瘤、少支胶质瘤、室管膜瘤、混合性胶质瘤、脉络丛瘤、来源不肯定的神经 上皮组织瘤、神经元及神经元神经胶质混合瘤、松果体实质肿瘤、胚胎性肿瘤、神经母细胞瘤肿瘤。
所述的功能性神经细胞或类神经细胞至少包括以下一项特征:
(1)类似神经细胞的形态;
(2)神经细胞特异性的基因表达水平上调;所述的上调表达的基因包括:DCX、Tuj1、Map2、NeuN、 Synapsin I中的一种或多种。
(3)胶质细胞特异的基因表达水平下调;所述的下调表达的基因包括:GFAP、S100β、Glast、Acsbg1 中的一种或多种。
(4)神经细胞特异的电生理特征,即所述细胞具有静息电位以及因兴奋性神经递质或抑制性神经递 质的作用而诱发的动作电位;所产生的细胞静息电位不高于-50mV,优选地,产生的细胞静息电位不高于 -55mV,或不高于-60mV,或不高于-65mV;所述的兴奋性神经递质包括但不限于谷氨酸(glutamate)或 红藻氨酸(kainate),可以诱导内向电流;所述的抑制性神经递质包括但不限于甘氨酸(glycine)或γ氨基 丁酸(GABA),可以诱导外向电流;
(5)形成功能性的突触;所述突触能够接受兴奋性或抑制性的信号传入,能输出动作电位。
本发明第二方面,提供了一种促进胶质细胞转分化,重编程为有功能的神经元或类神经元的方法。
所述的胶质细胞为任何来自人或非人哺乳动物的星形胶质细胞、NG2胶质细胞、少突胶质细胞、小 胶质细胞、或处于损伤状态下的胶质细胞、胶质细胞来源的肿瘤细胞等;所述的损伤状态下的胶质细胞为 组织或胶质细胞周边环境处于机械性的创伤、中风或神经退行性疾病引起的神经元死亡、凋亡从而致使神 经信号传导受阻或紊乱状态下的胶质细胞;所述胶质细胞来源的肿瘤细胞一般为胶质瘤细胞,选自来源于 人或非人哺乳动物的星形细胞瘤、少支胶质瘤、室管膜瘤、混合性胶质瘤、脉络丛瘤、来源不肯定的神经 上皮组织瘤、神经元及神经元神经胶质混合瘤、松果体实质肿瘤、胚胎性肿瘤、神经母细胞瘤肿瘤。
任何可促进胶质细胞转分化的转录因子表达增高的方法,包括但不限于将诱导因子或促进转录因子表 达的功能性片段通过与所述胶质细胞直接接触、或导入的方式,促进胶质细胞中任一NeuroD1、Brn2、 Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、Otx2转录因子的表达增高,并促进所述的胶质细胞展现 出功能性神经细胞或类神经细胞的特征;
所述诱导因子或促进转录因子表达的功能性片段可以是编码所述转录因子的多核苷酸,或多核苷酸转 译后的功能性的蛋白、多肽,或促进NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、 Otx2任一转录因子表达小分子药物、大分子药物、核酸药物,或位于所述NeuroD1、Brn2、Ascl1、Ngn2、 Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、Otx2任一转录因子上游调控转录因子表达上调的多核苷酸或功能性蛋 白、多肽、小分子药物或大分子药物、核酸药物等,通过胶质细胞被动吸收或通过递送系统到达胶质细胞 内部起效;
所述的递送系统包括但不限于载有所述诱导因子或促进转录因子表达的功能性片段的表达载体、包裹 有所述诱导因子或促进转录因子表达的功能性片段的纳米颗粒、包裹有所述诱导因子或促进转录因子表达 的功能性片段的外泌体、包裹有所述诱导因子或促进转录因子表达的功能性片段的细胞载体(如改造红细 胞或细菌等)或病毒载体、挂载有所述诱导因子或促进转录因子表达的功能性片段的靶向效应物(如胶质 细胞特异性抗体、多肽或其他靶向物质等);
在一优选例中,所述的诱导因子或促进转录因子表达的功能性片段为编码转录因子的多核苷酸,所述 的多核苷酸选自NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2的转录因子 功能性多核苷酸;所述的多核苷酸需要装载在病毒性或非病毒性的递送系统中;
在另一优选例中,所述的递送系统包括但不限于质粒、病毒、细胞载体;优选为病毒载体,包括 但不限于腺病毒载体、腺相关病毒载体(AAV)、逆转录病毒表达载体或慢病毒载体等;
在一优选例中,所述的载有转录因子多核苷酸的表达载体中还载有胶质细胞特异性的启动子,所述的 启动子,包括但不限于GFAP启动子、NG2启动子、Aldh1L1启动子、IBA1启动子、CNP启动子、LCN2 启动子或经过基因工程改造后的启动子变体。
在另一优选例中,所述的启动子为GFAP启动子,或经基因工程改造后的GFAP启动子。更优地,人 hGFAP启动子(SEQ ID No:42)可改造为683bp的截短型(SEQ ID No:43)。
在一优选例中,所述的载有转录因子多核苷酸的的表达载体中还载有一个或多个调控基因表达的 调控元件,用于增强基因的表达水平,包括但不限于CMV的增强子、SV40增强子、EN1增强子、VP16 融合蛋白或经过基因工程改造后的增强子变体,以及SV40 polyA加尾信号、人胰岛素基因polyA加尾信 号或者WPRE(土拨鼠乙肝病毒转录后调控元件)、人源性MAR序列或经过基因工程改造后的变体。
在另一优选例中,用于增强表达的调控元件为来自单纯疱疹病毒(Herpessimplex virus)的VP16蛋 白的激活结构域(SEQ ID NO:44),其中,所述VP16的编码序列(SEQ ID NO:45)可以单个装载或成 串装载,通过胶质细胞特异的启动子,表达VP16-转录因子的DNA结合区域融合蛋白。
在另一优选例中,用于增强表达的调控元件来自猴空泡病毒40(Simianvacuolating virus 40)SV40 的增强子(SEQ ID NO:46),将其插入到胶质细胞特异性启动子之前,可以增强启动子的活性,提高神经 元诱导效率。
在一优选例中,所述的载有转录因子多核苷酸的的表达载体中还可以同时载有其他功能性片段,所述 的其他功能性片段可以是报告基因或其他具有重编程功能的转录因子功能性片段,包括但不限于选自 NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、Otx2等;优选的在同一载体中可载有 至少2个转录因子的多核苷酸片段,所述的两个转录因子的多核苷酸可以在一个胶质细胞特异的启动子之 下表达,或者在两个胶质细胞特异的启动子之下分别表达。所述的两个转录因子的组合,分别选自NeuroD1 与Brn2的转录因子的组合、Gsx1与Tbr1的转录因子的组合、Dlx2与Ptf1a的转录因子组合、Pax6与Otx2的转录因子组合,两个转录因子的表达量的摩尔浓度比为4:1~1:4;优选地两种转录因子的表达量的摩尔 浓度比为2:1~1:2;最优地,两种转录因子的表达量的最优摩尔浓度比例为1:1。
在另一优选例中,在同一载体中载有至少2个转录因子,且其中一个转录因子为Ascl1或Ngn2, 则Ascl1或Ngn2的表达量的摩尔浓度比例不应低于20%,优选地,Ascl1或Ngn2的表达量的摩尔浓度比 例不应低于33%;最优地,Ascl1或Ngn2的表达量的摩尔浓度比例不应低于50%;并包括以下任一转录 因子的组合:(1)Ascl1与其他任一转录因子的组合,另一转录因子选自NeuroD1、Brn2、Ascl1、Ngn2、 Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2;(2)Ngn2与其他任一转录因子的组合,另一转录因子选自NeuroD1、 Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2;(3)当在同一载体中载有至少3个转录 因子时,所述转录因子至少包含Ascl1+NeuroD1+Brn2的组合、Ascl1+Gsx1+Tbr1的组合、Ascl1+Dlx2+Ptf1a 的组合、Ascl1+Pax6+Otx2的组合或Ngn2+NeuroD1+Brn2的组合、Ngn2+Gsx1+Tbr1的组合、 Ngn2+Dlx2+Ptf1a的组合、Ngn2+Pax6+Otx2的组合,其中,除Ascl1或Ngn2以外的另外两个转录因子的 表达量的摩尔浓度比为4:1~1:4;优选地两种转录因子的表达量的摩尔浓度比为2:1~1:2;最优地,两种 转录因子的表达量的最优摩尔浓度比例为1:1;
在另一优选例中,还可以同时使用载有不同转录因子多核苷酸的一个或多个表达载体,所述的转录因 子选自NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2的转录因子功能性多 核苷酸;优选的载体组合选自分别载有的转录因子NeuroD1与载有转录因子Brn2的载体组合、载有转录 因子Gsx1与载有转录因子Tbr1的载体组合、载有转录因子Dlx2与载有转录因子Ptf1a的载体组合、载 有转录因子Pax6与载有转录因子Otx2的载体组合,其中两种转录因子的表达量的摩尔浓度比为4:1~1:4; 优选地两种转录因子的表达量的摩尔浓度比为2:1~1:2;最优地,两种两种转录因子的表达量的最优摩尔 浓度比例为1:1;
在另一优选例中,还可以同时使用载有不同转录因子多核苷酸的一个或多个表达载体,至少包含载有 Ascl1或载有Ngn2多核苷酸的表达载体与其他转录因子的载体组合,其中Ascl1或Ngn2的表达量的摩尔 浓度比例不应低于20%,优选地,Ascl1或Ngn2的表达量的摩尔浓度比例不应低于33%;最优地,Ascl1 或Ngn2的表达量的摩尔浓度比例不应低于50%;且选自以下任一载体的组合:(1)载有转录因子Ascl1 与载有另一转录因子的载体组合,所述另一转录因子选自NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、 Dlx2、Ptf1a、Pax6或Otx2;(2)载有转录因子Ngn2与载有另一转录因子的载体组合,所述另一转录因 子选自NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2;(3)载有转录因子Ascl1、载有转录因子NeuroD1与载有转录因子Brn2的载体组合,载有转录因子Ascl1、载有转录因子Gsx1与载 有转录因子Tbr1的载体组合,载有转录因子Ascl1、载有转录因子Dlx2与载有转录因子Ptf1a的载体组 合,载有转录因子Ascl1、载有转录因子Pax6与载有转录因子Otx2的载体,或载有转录因子Ngn2、载有 转录因子NeuroD1与载有转录因子Brn2的载体组合,载有转录因子Ngn2、载有转录因子Gsx1与载有转 录因子Tbr1的载体组合、载有转录因子Ngn2、载有转录因子Dlx2与载有转录因子Ptf1a的载体组合、载 有转录因子Ngn2、载有转录因子Pax6与载有转录因子Otx2的载体组合,其中,除Ascl1或Ngn2以外的 另外两个转录因子的表达量的摩尔浓度比为4:1~1:4;优选地两种转录因子的表达量的摩尔浓度比为2:1~ 1:2;最优地,两种转录因子的表达量的最优摩尔浓度比例为1:1;
在一优选例中,所述的载有转录因子多核苷酸的功能性片段的表达载体为慢病毒载体;慢病毒载体载 有病毒ITR序列、CAG启动子、转录因子多核苷酸的功能性片段的编码框以及转录后调控元件WPRE等; 所述的表达载体还可以载有报告基因,但报告基因在实际应用中不是必需的,如所述的慢病毒载体自5' 到3'端可依次包括以下元件:病毒ITR序列+CAG启动子+转录因子多核苷酸和绿色荧光蛋白GFP的编 码框+转录后调控元件WPRE+病毒ITR序列+氨苄抗性基因的启动子和编码框,其中绿色荧光蛋白GFP 的编码框与氨苄抗性基因的启动子和编码框不是必需的。优选地,所述的转录因子的多核苷酸选自编码 NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2的功能性多核苷酸,具体地, 选自SEQ ID NO.:3、4、7、8、11、12、15、16、19、20、23、24、27、28、31、32、35、36、39和/或 40的序列。
在一优选例中,所述的载有转录因子多核苷酸的功能性片段的表达载体为GFAP-AAV载体; GFAP-AAV载体载有病毒ITR序列、CMV的增强子、人GFAP的启动子、转录因子多核苷酸的功能性片 段的编码框以及转录后调控元件WPRE等;所述的表达载体还可以载有报告基因,但报告基因在实际应 用中不是必需的,如所述的GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+CMV 的增强子+人GFAP的启动子+转录因子多核苷酸和红色荧光蛋白mCherry的编码框+转录后调控元件 WPRE+病毒ITR序列+氨苄抗性基因的启动子和编码框,其中红色荧光蛋白mCherry的编码框与氨苄抗性 基因的启动子和编码框不是必需的。优选地,所述的转录因子的多核苷酸选自编码NeuroD1、Brn2、Ascl1、 Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2的功能性多核苷酸,具体地,选自SEQ ID NO.:3、4、7、8、11、12、15、16、19、20、23、24、27、28、31、32、35、36、39和/或40的序列。
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+SV40的增强 子+人GFAP的启动子+转录因子多核苷酸+转录后调控元件WPRE+病毒ITR序列;
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+CMV的增强 子+人GFAP的启动子+VP16融合蛋白+转录因子转录因子的DNA结合区域+转录后调控元件WPRE+病 毒ITR序列;
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+CMV的增强 子+人截短型GFAP的启动子+转录因子多核苷酸+转录后调控元件WPRE+病毒ITR序列;
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+SV40的增强 子+人截短型GFAP的启动子+VP16融合蛋白+转录因子转录因子的DNA结合区域+转录后调控元件 WPRE+病毒ITR序列;
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+SV40的增强 子+人截短型GFAP的启动子+转录因子多核苷酸+转录后调控元件WPRE+病毒ITR序列;
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+SV40的增强 子+人GFAP的启动子+VP16融合蛋白+转录因子的DNA结合区域+转录后调控元件WPRE+病毒ITR序 列;
在另一优选例中,GFAP-AAV表达载体自5'到3'端可依次包括以下元件:病毒ITR序列+CMV的增强 子+人截短型GFAP的启动子+VP16融合蛋白+转录因子的DNA结合区域+转录后调控元件WPRE+病毒 ITR序列;
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括(A)本发明第一方面所述的促 进转录因子表达的功能性片段;利用本发明第二方面所述的促进胶质细胞转分化,重编程为有功能的神经 元或类神经元的方法,和(C)药学上可接受的辅料。
本发明第四方面,提供了本发明第三方面所述的药物组合物的用途,所述的药物组合物可用于制备针 对神经系统疾病基因疗法的药物,优选地,所述的神经系统疾病为神经系统损伤或胶质细胞来源的胶质瘤。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征 之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
与现有技术相比,本发明主要存在以下竞争性优势:
(1)创新性地获得了一批具有重编程功能的转录因子,并摸索了转录因子及其组合转分化的能力, 潜在可以应用于不同的场景。
(2)探索了转录因子及其组合的应用场景,可以应用于神经系统疾病和肿瘤的研究。
(3)进一步改造了用于基因治疗的转录因子的表达元件,显著提高转录因子促进胶质细胞转分化为 神经元的效率。
附图说明
图1显示Brn2和NeuroD1的组合能将人神经胶质瘤细胞诱导成神经元。图1A-C分别显示在对照慢病 毒FUGW,单种病毒FUGW-NeuroD1以及两种病毒FUGW-Brn2和FUGW-NeuroD1的组合感染人神经 胶质瘤细胞U251细胞14天后,免疫荧光显示神经元特性标志分子Tuj1的表达情况。图1D显示的是是 不同病毒诱导神经元比率的统计图。"**"代表p<0.01。标尺:50um。
图2显示Brn2和NeuroD1的组合诱导神经元的分子表达属性。图2A显示胶质瘤细胞感染慢病毒21天 后,诱导的神经元表达成熟神经元的标志分子MAP2。图2B-D显示的是诱导的神经元表达成熟神经元的 标志分子Synapsin I。图2E-H显示的是诱导的神经元的递质属性,表达谷氨酸能神经元标志分子VGLUT1。 标尺:20um。
图3显示Brn2和NeuroD1的组合诱导神经元的电生理属性。图3A显示的是玻璃电极正在记录的细胞 (带绿色荧光)。图3B显示的是诱导神经元能够发放动作电位。图3C显示的是检测到诱导神经元的突触 后电流信号,加入阻断剂CNQX和AP5后突触后电流信号消失。
图4显示Brn2和NeuroD1的组合诱导神经元退出细胞周期。图4A,B显示的是病毒感染不同时间段进 行BrdU间隔掺入标记时,Brn2/NeuroD1的组合诱导的细胞BrdU阳性数量急剧减少。图4C-F显示的是 病毒感染5天后连续BrdU掺入标记时,Brn2/NeuroD1的组合诱导的细胞BrdU阳性数量明显降低。图4F 箭头指示的是诱导的神经元是BrdU阴性的。"*"代表p<0.05。"**"代表p<0.01。标尺:50um。
图5显示Brn2和NeuroD1的组合抑制胶质瘤细胞的生长。图5A-C显示的是病毒感染14天后,针对 Ki67的免疫细胞化学分析显示Brn2/NeuroD1的组合中Ki67阳性的细胞数量明显减少。图5B箭头指示的 是诱导的神经元是Ki67阴性的。图5D显示的是病毒感染不同时间后统计的细胞数目。"**"代表p<0.01。 标尺:50um。
具体实施方式
本发明人经过广泛而深入的研究,发现了一批具有转分化重编程功能的转录因子或转录因子的组合以 及将胶质细胞转分化为神经元的方法,能够在体外或体内高效地将胶质细胞转分化为有电生理功能的神经 元,基于这样的发现,本发明人进一步探索了将此方法应用在探索神经损伤修复或脑胶质瘤药物开发的应 用上,特别是在胶质瘤动物模型上,观察到重编程导致胶质瘤细胞退出细胞周期,动物的肿瘤大小明显缩 小,生存时间明显延长。因此,这一批具有转分化重编程功能的转录因子或转录因子的组合,有望应用于神经损伤修复药物或胶质瘤药物的开发中。
转录因子
本发明所述的转录因子为神经细胞分化所必需的一种或一组转录因子。
NeuroD1功能性片段,为来源于哺乳动物、编码Neurogenic differentiation 1转录因子的多核苷酸或其表 达蛋白片段,NeuroD1为bHLH(basic helix-loop-helix)类转录因子,如来自人的NeuroD1分子在GenBank 的ID#为4760,其蛋白序列如SEQ ID NO.:1所示;NCBI Reference Sequence:NM_002500.5,CDS序列如 SEQ ID NO.:3所示。
Brn2功能性片段,又名POU3F2、Oct7、N-Oct3为来源于哺乳动物、编码Pou class3homeobox 2转录 因子的多核苷酸或其表达蛋白片段,Brn2为神经细胞特异的POU-III型转录因子家族,如来自人的Brn2 分子在GenBank的ID#为5454,其蛋白序列如SEQ ID NO.:5所示;NCBI Reference Sequence: NM_005604.4;CDS序列如SEQ ID NO.:7所示。
Ascl1功能性片段,为来源于哺乳动物、编码Achaete-scute homolog 1转录因子的多核苷酸或其表达 蛋白片段,Ascl1为bHLH(basic helix-loop-helix)类转录因子,如来自人的Ascl1分子在GenBank的ID# 为429,其蛋白序列如SEQ ID NO.:9所示;NCBIReference Sequence:NM_004316.4,CDS序列如SEQ ID NO.:11所示。
Ngn2功能性片段,又名Neurog2,为来源于哺乳动物、编码Neurogenin-2转录因子的多核苷酸或其 表达蛋白片段,Ngn2为bHLH(basic helix-loop-helix)类转录因子,如来自人的Ngn2分子在GenBank的 ID#为63973,其蛋白序列如SEQ ID NO.:13所示;NCBIReference Sequence:NM_024019.4,CDS序列如 SEQ ID NO.:15所示。
Gsx1功能性片段,又名Gsh1,为来源于哺乳动物、编码GS homeobox 1转录因子的多核苷酸或其表 达蛋白片段,Gsx1在DNA序列的结合位点为5'-GC[TA][AC]ATTA[GA]-3',如来自人的Gsx1分子在 GenBank的ID#为219409,其蛋白序列如SEQ ID NO.:17所示;NCBIReference Sequence:NM_145657.3, CDS序列如SEQ ID NO.:19所示。
Tbr1功能性片段,为来源于哺乳动物、编码T-box brain transcription factor1转录因子的多核苷酸或其 表达蛋白片段,Tbr1为T-box类转录因子,如来自人的Tbr1分子在GenBank的ID#为10716,其蛋白序列 如SEQ ID NO.:21所示;NCBI Reference Sequence:NM_006593.4,CDS序列如SEQ ID NO.:23所示。
Dlx2功能性片段,为来源于哺乳动物、编码distal-less homeobox 2转录因子的多核苷酸或其表达蛋白 片段,Dlx2为参与中间神经元的终末分化的转录因子,如来自人的Dlx2分子在GenBank的ID#为1746, 其蛋白序列如SEQ ID NO.:25所示;NCBI ReferenceSequence:NM_004405.4,CDS序列如SEQ ID NO.:27 所示
Ptf1a功能性片段,为来源于哺乳动物、编码pancreas associatedtranscription factor 1a转录因子的多核 苷酸或其表达蛋白片段,Ptf1a为参与胰腺发育的转录因子,如来自人的Ptf1a分子在GenBank的ID#为 256297,其蛋白序列如SEQ IDNO.:29所示;NCBI Reference Sequence:NM_178161.3,CDS序列如SEQ ID NO.:31所示。
Pax6功能性片段,为来源于哺乳动物、编码paired box 6转录因子的多核苷酸或其表达蛋白片段,Pax6 为参与神经组织发育关键的转录因子,如来自人的Pax6分子在GenBank的ID#为5080,其蛋白序列如 SEQ ID NO.:33所示;NCBI Reference Sequence:NM_000280.5,CDS序列如SEQ ID NO.:35所示。
Otx2功能性片段,为来源于哺乳动物、编码orthodenticle homeobox 2转录因子的多核苷酸或其表达 蛋白片段,Otx2属于bicoid同源结构域亚家族转录因子,如来自人的Otx2分子在GenBank的ID#为5015, 其蛋白序列如SEQ ID NO.:37所示;NCBI ReferenceSequence:NM_001270523.2,CDS序列如SEQ ID NO.:39所示。
任何可促进上述转录因子的功能性片段表达增高的方法,没有特殊限制,包括但不限于将诱导因子或 促进转录因子表达的功能性片段通过与所述胶质细胞直接接触、或导入的方式,促进胶质细胞中任一 NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、Otx2转录因子的表达增高或活性增高, 并促进所述的胶质细胞展现出功能性神经细胞或类神经细胞的特征;所述诱导因子或促进转录因子表达 的功能性片段可以是编码所述转录因子的多核苷酸,或多核苷酸转译后的功能性的蛋白、多肽,或促进 NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、Otx2任一转录因子表达小分子药物、 大分子药物、核酸药物,或位于所述NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、 Otx2任一转录因子上游调控转录因子表达上调的多核苷酸或功能性蛋白、多肽、小分子药物或大分子药 物等,通过胶质细胞被动吸收或通过递送系统到达胶质细胞内部起效;
所述的促进上述转录因子的功能性片段表达增高的方法,还可以是通过CRISPR/dCas9靶向相关转录 因子的DNA激活基因的表达获得,或者通过CRISPR/Cas13靶向相关转录因子RNA提高转录因子功能性 蛋白的表达获得;
本领域技术人员可以根据现有的数据库对上述转录因子的促进方法进行筛选。应理解,基于本发明公 开的转录因子对胶质细胞转分化的功能以及对神经损伤修复和胶质瘤细胞的抑制作用,本领域技术人员能 够合理地预见任何对上述转录因子具有促进作用的物质均会对胶质细胞转分化以及对神经损伤修复和胶 质瘤细胞的抑制有功能。
胶质瘤细胞
神经胶质瘤简称胶质瘤,也称为胶质细胞瘤,广义是指所有神经上皮来源的肿瘤,狭义是指源于各类 胶质细胞的肿瘤。胶质瘤是致死率最高的恶性肿瘤之一,也是最常见的原发性中枢神经系统肿瘤,占脑和 中枢神经系统肿瘤的30%、占脑恶性脑肿瘤的80%,是人类健康的严重威胁。根据世界卫生组织 (WHO)1999年的分类方案分为星形细胞瘤、少支胶质瘤、室管膜瘤、混合性胶质瘤、脉络丛瘤、来源不 肯定的神经上皮组织瘤、神经元及神经元神经胶质混合瘤、松果体实质肿瘤、胚胎性肿瘤、神经母细胞瘤 肿瘤。
可用于本发明的胶质瘤细胞没有特别限制,包括哺乳动物中枢神经系统来源的各种胶质瘤,例如来源 于星形细胞瘤、少支胶质瘤、室管膜瘤或神经母细胞瘤,较佳地,来源于星形细胞瘤或神经母细胞瘤。
在本发明中,具有转分化功能的转录因子以及转录因子的组合对胶质瘤细胞所具有的诱导转化为神经 元/类神经元的能力,且表现出神经元细胞特有的标志物,DCX、Tuj1、Map2、NeuN、Synapsin I。同时 引起胶质细胞瘤的增殖明显降低,肿瘤生长减慢,恶性化程度下降。
递送系统
可用于本发明的递送系统没有特殊限制,可以是含有所述编码所述转录因子的多核苷酸序列进入胶质 细胞或胶质瘤细胞的表达载体。如病毒载体,其可以是任何能够利用病毒具有传送其基因组的特点,将遗 传物质带入其他细胞,进行感染的病毒载体。可发生于完整活体或是细胞培养中。包括慢病毒载体、腺病 毒载体、腺相关病毒载体、疱疹病毒载体、痘病毒载体等。
递送系统还可以是新型纳米颗粒,用于装载所述转录因子的功能性片段或促进所述转录因子表达增高 或活性增强的分子实体,递送到目标细胞周边或进入到目标细胞中,如脂质体纳米颗粒、金属纳米颗粒、 高分子纳米颗粒等递送系统。
递送系统还可以是包裹有所述转录因子的功能性片段或促进所述转录因子表达增高或活性增强的分 子实体的外泌体,或者是包裹有转录因子的功能性片段或促进所述转录因子表达增高或活性增强的分子实 体的改造红细胞或细菌。
此外,递送系统还可以结合上靶向功能的分子,如靶向胶质细胞或胶质瘤细胞的特异性单克隆抗体、 多肽等,可以更好地促进所述转录因子的功能性片段或促进所述转录因子表达增高或活性增强的分子实体 功能性片段在胶质细胞或胶质瘤细胞上的靶向性,增加诱导胶质细胞转分化和抗肿瘤效率。
诱导方法
本发明还提供了在体外和体内将胶质细胞或胶质瘤细胞诱导转分化为神经元细胞或类神经元细胞,进 而达到神经修复或抗肿瘤目的的方法。
在体外,可将含有所述转录因子的功能性片段、促进转录因子功能性片段表达或活性增强的分子实体、 含有所述转录因子功能性片段或促进转录因子功能性片段表达和活性增强的分子实体的递送系统,通过接 触或施用(例如注射)到体外培养的目的细胞,使胶质细胞被动吸收或通过递送系统到达胶质细胞内部起效, 以实现神经元的体外分化,且抑制肿瘤细胞的增殖。在体外转分化成功的细胞团还可以通过移植的方式实 现神经损伤部位的神经修复。
在体内,可将含有所述转录因子的功能性片段、促进转录因子功能性片段表达或活性增强的分子实体、 含有所述转录因子功能性片段或促进转录因子功能性片段表达和活性增强的分子实体的递送系统,通过接 触或施用(例如注射)到神经损伤部位或肿瘤病灶,使胶质细胞被动吸收或通过递送系统到达胶质细胞内部 起效,以实现神经元的体外分化,且抑制肿瘤细胞的增殖。直接在体内诱导的方法,将有助于神经损伤的 原位修复以及肿瘤的原位抑制。
同时,结合分子靶向技术,在载有所述转录因子功能性片段或促进转录因子功能性片段表达和活性增 强的分子实体的递送系统上安装胶质细胞或胶质瘤特异性的分子靶向物,则可以通过异位注射的方法实现 神经元转分化的诱导。
药物组合物以及给药方式
本发明还提供的一种药物组合物为含有任何促进所述转录因子功能性片段的表达或活性增强的分子 实体或含有所述转录因子功能性片段或促进转录因子功能性片段表达和活性增强的分子实体的递送系统, 或在体外所述转录因子功能性片段或促进转录因子功能性片段表达和活性增强的分子实体转分化后的功 能性神经元团,以及其他药学上可接受的载体。
在本发明的药物组合物,通常含有1010-1013PFU/ml的AAV病毒颗粒,较佳地1011-1013PFU/ml的AAV 病毒颗粒,更佳地1010-1012PFU/ml的AAV病毒颗粒。
在本发明的药物组合物,通常含有107-1010PFU/ml的慢病毒颗粒,较佳地107-109PFU/ml的慢病毒颗 粒,更佳地108-109PFU/ml的慢病毒颗粒。
药学上可接受的载体”指用于治疗剂给药的载体,包括各种赋形剂和稀释剂。
术语指这样一些药剂载体:它们本身并不是必要的活性成分,且施用后没有过分的毒性。合适的载体 是本领域普通技术人员所熟知的。在组合物中药学上可接受的载体可含有液体,如水、盐水、缓冲液。另 外,这些载体中还可能存在辅助性的物质,如填充剂、润滑剂、助流剂、润湿剂或乳化剂、pH缓冲物质 等。所述的载体中还可以含有细胞转染试剂。
通常,将所述表达载体和药学上可接受的载体混合后,即可获得的本发明的药物组合物。
本发明所述的组合物的给药方式没有特别限制,代表性的例子包括(但并不限于):静脉注射、皮下注 射、脑部注射、鞘内注射和脊髓注射等。
应用
本发明所述的含有任何促进所述转录因子功能性片段的表达或活性增强的分子实体或含有所述转录 因子功能性片段或促进转录因子功能性片段表达和活性增强的分子实体的递送系统或功能性神经团可用 于制备神经损伤修复或抑制胶质细胞瘤增殖与恶化的药物。
本发明有益效果
本发明创新性地获得了一批具有重编程功能的转录因子,并摸索了转录因子及其组合转分化的能力, 潜在可以应用于不同的场景:如针对神经的损伤修复,可以根据损伤情况,有选择性地使用中高效率的转 录因子以及转录因子的组合(Ascl1或NeuroD1);而针对胶质细胞瘤,则需要更高的转化效率的转录因子 和转录因子组合(Ascl1或Ascl1与Ngn2的组合),以实现快速地下调胶质细胞瘤的恶性程度。
在研究中,本发明还进一步改造了用于基因治疗的转录因子的表达元件,显著提高转录因子促进胶质 细胞转分化为神经元的效率。特别地,本发明将所使用的转录因子的组合能够将人胶质瘤细胞转分化为神 经元,并导致胶质瘤细胞退出细胞周期,进而不再增殖生长。在胶质瘤模型中,注射含所述转录因子组合 的腺相关病毒,能显著缩小肿瘤大小,延长动物生存时间。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发 明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克 隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建 议的条件。
通用方法
人胶质瘤细胞培养
对于人胶质瘤细胞系U251和U87细胞(购买自中科院上海生命科学研究院细库),在37℃下在含5% CO2的培养箱中,培养液为含10%胎儿牛血清和1%青霉素/链霉素的DMEM培养基。加入慢病毒感染后, 感染12小时后后全换液成诱导培液(DMEM,2%B-27,1%PS),48h后再次全换液成神经培养液 DMEM/F-12,2%B-27,1%PS,20ng/ml BDNF,20ng/mlGDNF。后续每三天换一半培养液。
免疫显色
培养细胞的免疫显色参照“Direct conversion of fibroblasts to functionalneurons by defined factors”(Vierbuchen,T.et al.Nature 463,1035-1041(2010))。组织切片的免疫显色实验参照已发表的方法进行。 免疫显色用到的一抗包括:mouse anti-NeuN(Millipore,1:100),rabbit anti-Dsred(Clontech,1:500),mouse anti-Tuj1(Covance,1:500),mouse anti-Map2(Sigma,1:500),rabbit anti-GFP(Invitrogen,1:1,000),chick anti-GFP(Invitrogen,1:1,000),rabbit anti-Synapsin I(Millipore,1:1,000),rabbit anti-VGLUT1(Synaptic Systems,1:500),rabbit anti-Ki67(1:200;RM-9106;Thermo Fisher Scientific),mouse anti-BrdU(1:200; B2531;Sigma)。FITC-,Cy3-以及Cy5-偶联的二抗购自Jackson Immunoresearch。
BrdU(5-溴脱氧尿嘧啶核苷)标记和细胞增殖实验
培养的人胶质瘤细胞加入10mM BrdU(Sigma)按实验需求孵育2h或者连续培养,BrdU的显色通过 anti-BrdU的抗体进行免疫检测。增殖的细胞也使用Ki67抗体检测。另外,评估胶质瘤细胞的生长实验时, 在24孔板中(5×104细胞/孔),不同时间点(第0、3、7、14和21天)对细胞数目进行计数统计。
胶质细胞转分化体外模型
(1)质粒构建与病毒感染
在FUGW–IRES–EGFP的载体模板(载体信息参考文献Efficient transfer,integration,and sustained long-term expression of the transgene in adult ratbrains injected with a lentiviral vector.Proc Natl Acad Sci U S A 93:11382–11388)上克隆人NG2启动子替换CAG启动子,再将所述转录因子的多核苷酸片段构建到该慢病毒载体上,以生成hNG2-转录因子-IRES-EGFP慢病毒质粒。慢病毒的包装参照文献“Production and purification of lentiviral vectors”(Tiscornia,G.,Singer,O.&Verma,I.M.Nat.Protoc.1,241-245(2006))。
NG2细胞铺板培养24小时后加入慢病毒,感染24小时后更换培养基:DMEM/F12,B27,Glutamax 和青霉素/链霉素。感染6-7后,每三天在培养基中加入脑源性神经营养因子(BDNF;PeproTech公司, 20ng/ml)。
(2)NG2细胞转分化为神经元
培养的小鼠NG2细胞大多数对NG2胶质细胞标记物NG2为免疫阳性,少量的细胞表达少突胶质细胞 的标志分子O4和CNPase,没有检测到神经元标志分子Tuj1以及干细胞标志分子Sox2和Oct4的 表达。
NG2细胞转染hNG2-转录因子-IRES-GFP慢病毒10天后,检测NG2细胞的神经元形态以及神经 元的标志分子Tuj1。感染慢病毒21天后,同时检测成熟神经元的标志分子NeuN和MAP2,以及通过 电生理记录具有神经元形态和阳性标记的细胞是否能产生动作电位,如果能记录到自发的突触后电流,则 说明这些神经元能形成功能性突触。
(3)NG2细胞诱导的神经元移植到体内可以存活
体外诱导得到的转分化神经元能否在体内存活并发挥功能是其是否可用于疾病治疗的关键。所述转 录因子在NG2细胞诱导的神经元移植到大脑皮层后,两周进行免疫组化实验,需要观察移植的细胞是 否能够依附在皮层边缘,并检测细胞是否形成神经突起伸向皮层更深处。同时通过免疫荧光共定位实验检 测移植的细胞是否表达神经元标志分子Tuj1、NeuN和MAP2等。
需要说明的是,除了NG2启动子,其他胶质细胞特异性的启动子均可以实现相似转分化的功能,尽 在转化效率上略有高低,为统一筛选,胶质细胞转分化体外模型统一在一个载体类型和同一启动子下进行。
胶质细胞转分化体内模型
(1)腺相关病毒质粒构建与病毒感染
在AAV–FLEX–Arch–GFP(Addgene,#22222)的载体模板上克隆GFAP启动子替换CAG启动子并保留 CMV增强子,再用mCherry的编码框取代GFP后得到AAV-mCherry质粒(对照组)。将所述转录因子 克隆进AAV-mCherry质粒后得到AAV-mNeurog2/mCherry质粒,目的基因在GFAP启动子作用下可 以特异靶向星形胶质细胞。
(2)星形胶质细胞转分化为神经元
将病毒AAV-mCherry或AAV-转录因子/mCherry注射到成年野生型小鼠的一侧顶盖,然后在不同的 时间点收集脑组织样品。在病毒注射3天和30天,观察对照病毒AAV-mCherry,与病毒AAV-转录因 子/mCherry的小鼠的mCherry是否与NeuN共定位。为了证明诱导神经元是有功能的活性神经元,同时 对AAV病毒感染的中脑电生理记录。在电压钳模式下记录内向Na+电流以及外向K+电流,统计被记录 的细胞动作电位发放的比例以及突触后电流(postsynaptic currents),并通过阻断剂NBQX来观察突触后电 流信号是否消失,以及洗脱后突触后电流信号是否出现,来判断被诱导的神经元是否整合到神经环路建 立突触联系,以判断是否是功能性的神经元。
所述AAV病毒参照小鼠脑图谱进行。注射病毒后,在不同时间点收集背部中脑、脊髓做免疫显色或 脑片记录。完整脊髓以及损伤脊髓病毒注射浓度,速度与每针注射量与脑区一致,在脊髓是以30°夹角的 方位注射的。
神经损伤修复模型
(1)脊髓损伤与病毒转染
构造小鼠T8-T10脊髓全断模型(参照McDonough A,Monterrubio A,Ariza J,etal.Calibrated Forceps Model of Spinal Cord Compression Injury.Jove-Journal ofVisualized Experiments 2015.的方法),损伤后立即 将AAV-mCherry病毒以及AAV-转录因子/mCherry分别注射到损伤脊髓两侧。在病毒注射3与注射病 毒后30天,观察mCherry是否与NeuN共定位。
(2)脊髓损伤修复检测
脊髓胸段损伤后导致感觉传入的缺失促使脑干的下行抑制系统的抑制作用减弱导致尾巴对外界刺激 过度敏感。我们利用甩尾实验模型,通过测量两组小鼠尾巴在48℃以及52℃的热刺激下反应延迟时间 来检测小鼠的感觉能力。根据BMS标准对小鼠运动功能进行评分。试验方法参照Basso Mouse Scale for locomotion detects differences inrecovery after spinal cord injury in five common mouse strains.J Neurotrauma,2006.23(5):p.635-59.
胶质瘤模型
胶质瘤模型移植所使用的小鼠为七周的NOD-scid小鼠。0.25%胰酶消化诱导3天或者没有经过诱导 的人胶质瘤细胞,离心去除上清使得细胞浓缩后密度大约为2.5×105cells/μl,每只小鼠大脑纹状体移植2 μl即总共5×105细胞。移植后3周进行组化或者一周后注射病毒,后续再进行免疫组化检测。
实施例1单转录因子的功能性片段促进胶质细胞转分化为神经元
首先,我们利用胶质细胞转分化体外模型,进行了初步的筛选,获得了一批可诱导胶质细胞转分化为 神经元的转录因子,所使用的转录因子编码序列以及转化效率如表1所示。表1中的转化效率为既有神经 元阳性标记物的共定位,又可检测到自发的突触后电流的阳性细胞数,在研究中,平均每个转录因子至少 测试不低于20个NeuN阳性的转分化细胞。
表1单转录因子的体外胶质细胞转分化效率
转录因子 | 人(野生型) | 转分化效率 | 小鼠(野生型) | 转分化效率 |
NeuroD1 | SEQ ID NO:1/3 | 42.3% | SEQ ID NO:2/4 | 45.8% |
Brn2 | SEQ ID NO:5/7 | 8.7% | SEQ ID NO:6/8 | 9.6% |
Ascl1 | SEQ ID NO:9/11 | 68.5% | SEQ ID NO:10/12 | 67.3% |
Ngn2 | SEQ ID NO:13/15 | 51.2% | SEQ ID NO:14/16 | 46.3% |
Gsx1 | SEQ ID NO:17/19 | 6.2% | SEQ ID NO:18/20 | 6.9% |
Tbr1 | SEQ ID NO:21/23 | 4.2% | SEQ ID NO:22/24 | 5.3% |
Dlx2 | SEQ ID NO:25/27 | 32.1% | SEQ ID NO:26/28 | 35.7% |
Ptf1a | SEQ ID NO:29/31 | 11.6% | SEQ ID NO:30/32 | 15.3% |
Pax6 | SEQ ID NO:33/35 | 25.2% | SEQ ID NO:34/36 | 19.8% |
Otx2 | SEQ ID NO:37/39 | 6.9% | SEQ ID NO:38/40 | 8.4% |
不论是人源的或鼠源的转录因子均具有将胶质细胞在体外转分化为神经元的能力。
在进一步研究中,我们还发现,针对人Ascl1蛋白,如果将其蛋白序列的5个保守的丝氨酸-脯氨酸(SP) 磷酸化位点(分别位于蛋白序列第93,190,194,207,223位)突变为丙氨酸-脯氨酸(AP)(增强型,蛋白序 列SEQ ID NO:41),则可以进一步将转化效率提高至85.5%水平。
实施例2单转录因子的功能性片段促进背侧中脑的胶质细胞转分化
根据胶质细胞转分化体内模型,我们尝试使用实施例1所筛选转录因子来诱导背侧中脑的胶质细胞, 如下表所示(表2),不同的转录因子展示了明显不同的转化效率。
表2单转录因子的体内胶质细胞转分化效率(序列如实施例1所示)
在体内模型的基础上,我们进一步对AAV表达载体的表达元件进行了详细的研究,至少发现三 种可以显著增加胶质细胞转化效率的技术改进。
(1)VP16融合蛋白的插入
VP16为来自单纯抱疫病毒(Herpes simplex virus)的VP16蛋白的激活结构域(SEQ ID NO:45), 我们将其基因序列克隆进AAV-转录因子/mCherry质粒后得到AAV-VP16-转录因子/mCherry质粒。VP16 可以是单个也可以是多个成串。质粒会翻译出融合蛋白VP16-转录因子,从而增强转录因子的激活基因表 达功能。AAV-VP16-转录因子/mCherry诱导的神经元效率明显高,而且诱导的速度更快(见表3)。
(2)启动子缩短
我们将人源的hGFAP启动子2.2kb(SEQ ID NO:42)改为683bp(SEQ ID NO:43),发现改造 的启动子没有影响靶向星形胶质细胞特异性的同时,提高了AAV的包装效率,降低了病毒包装的空壳率, 得到的AAV滴度更高更纯。在体内诱导时,Short-hGFAP-AAV-转录因子/mCherry能够提高了病毒的转染 效率,降低细胞的死亡数量,使诱导过程更为安全(见表3)。
(3)增强子插入
我们将猴空泡病毒40(Simian vacuolating virus 40)SV40的增强子(SEQ IDNO:46)插入 hGFAP-AAV-转录因子/mCherry质粒得到SV40-hGFAP-AAV-转录因子/mCherry。SV40的增强子能大大增 强hGFAP启动子的活性,从而使目的基因能够高效地在体内表达,从而使神经元诱导效率提升(见表3)。
上述三种增强表达的方法,可以单独使用也可俩俩联合或三者同时使用。对本实施例中所述的转录因 子都可以起到诱导效率的提升,以人Ascl1为例,见表3。
表3 Ascl1转化效率的提高
转录因子 | 序列 | VP16插入 | 启动子截短 | SV40插入 |
野生型hAscl1 | SEQ ID NO:9 | 75.8% | 77.2% | 76.4% |
增强型hAscl1 | SEQ ID NO:41 | 88.4% | 89.2% | 88.9% |
同样地,针对其他转录因子,在上述三种任一的技术方案,都可以明显提高转化效率或AAV的滴度, 表4展示了其他转录因子使用上述改造策略之后的平均转化效率。
表4表达载体的改造策略对转分化效率的影响
转录因子 | 序列 | VP16插入 | 启动子截短 | SV40插入 |
hNgn2 | SEQ ID NO:13 | 73.8% | 74.2% | 74.4% |
hNeuroD1 | SEQ ID NO:1 | 68.3% | 69.6% | 68.5% |
hDlx2 | SEQ ID NO:25 | 25.3% | 26.3% | 25.4% |
实施例3转录因子的功能性片段组合进一步增加了胶质细胞转分化效率
根据胶质细胞体外以及体内转分化模型,并结合实施例2中所述的载体改造策略,我们首先把所筛选 到的转录因子展开随机的俩俩组合。其中,不同的转录因子可以在同一载体中同时表达,或者分别表达在 不同的表达载体中,下表所述的表达比例为实际研究中所表达的功能蛋白的摩尔浓度比。在NeuroD1、 Brn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6、Otx2转录因子中,我们意外获得了几组单转录因子效率不高, 但组合时可明显提高转录因子效率的组合,而且表达功能蛋白的摩尔浓度比例越接近,所获的的转化效率 高(见表5)。
表5转录因子组合可提高胶质细胞转分化的效率(转分化体外模型,序列选自实施例1人源序列)
在研究中,我们还发现,Ascl1与Ngn2是两个关键转录因子,与上述任一转录因子或转录因子 组合联用,均可实现明显的转录效率的增强;且实现了叠加增效的功能(见表6与表7)。
表6关键转录因子Ascl1可显著增强胶质细胞转分化效率(转分化体外模型,序列选自实施例1人源 序列)
表7关键转录因子Ngn2可显著增强胶质细胞转分化效率(转分化体外模型,序列选自实施例1人源 序列)
在上述研究中,不论是人源的或鼠源的转录因子及其组合均能增加胶质细胞转分化为神经元的效率。
实施例4转录因子及其组合在脊髓损伤修复中的应用
脊髓损伤(Spinal cord injury,SCI)是一类中枢神经受损疾病,伴随着脊髓神经元的死亡以及胶质疤痕 的形成。在体神经元重编程将星形胶质细胞转化为神经元,有可能可以缓解SCI造成的伤害,有望成为 新的治疗手段。
根据神经损伤修复模型,我们发现实施例1-3中所述的转化效率在50%以上转录因子或转录因子 组合均有诱导损伤部位胶质细胞获得电生理特征的能力,而且能够接受外来信号输入。根据脊髓损伤检测 模型,我们发现这些转录因子重编程神经元对脊髓损伤小鼠感觉功能以及运动功能的恢复有很大帮助,特 别是实施例1-3所述转化效率达到75%以上的转录因子或转录因子组合。示例的优选转录因子及其组合如 表8。
表8优选的神经损伤修复的转录因子及其组合
实施例5转录因子功能性片段的组合在体外胶质瘤细胞转分化为神经元
在获得如实施例1-3的转录因子及其组合的基础上,我们还探索了高转化效率的转录因子或转录因子 组合可促进胶质瘤细胞转分化为神经元中的应用实施方案与胶质细胞体内或体外转分化模型类似,以 NeuroD1和Brn2的因子组合为例,具体实施如下:
(1)质粒构建与病毒感染
在FUGW–IRES–EGFP的载体模板(载体信息参考文献Efficient transfer,integration,and sustained long-term expression of the transgene in adult ratbrains injected with a lentiviral vector.Proc Natl Acad Sci U S A 93:11382–11388)上,将多核苷酸功能性片段构建到该慢病毒载体上,以生成携带有多核苷酸功能性片 段的慢病毒质粒。在一实施例中,将源自人NeuroD1转录因子片段(SEQ ID NO:3)构建到该慢病毒载 体上,以生成hNeuroD1-IRES-EGFP慢病毒质粒。慢病毒的包装参照文献“Production and purification of lentiviral vectors”(Tiscornia,G.,Singer,O.&Verma,I.M.Nat.Protoc.1,241-245(2006))。
人胶质瘤细胞铺板培养24小时后加入慢病毒,感染24小时后更换培养基:DMEM/F12,B27,Glutamax 和青霉素/链霉素。感染6-7后,每三天在培养基中加入脑源性神经营养因子(BDNF;PeproTech公司, 20ng/ml)。
(2)NeuroD1将胶质瘤细胞转分化为神经元
培养的人胶质瘤细胞U251感染hNeuroD1-IRES-EGFP慢病毒14天后,通过细胞免疫荧光我们发现, 有部分的Tuj1阳性细胞出现,并展现神经元的形态(图1B,D),说明NeuroD1单独能将将胶质瘤细胞 U251转分化为神经元,其转化效率为5.1。
(3)NeuroD1和Brn2共表达提高了胶质瘤细胞转分化为神经元的效率
虽然NeuroD1单独能将胶质瘤细胞转分化为神经元,但是其诱导效率并不是非常高。为了提高诱导 效率,测试了其它转录因子,发现NeuroD1和Brn2(SEQ ID NO:7)一起能够非常高效地将胶质瘤细胞 U251转分化为神经元,并且细胞呈现成熟神经元的形态(图1C,D)转化效率为。我们还测试了另外一 种人胶质瘤细胞U87,发现NeuroD1和Brn2也能够非常高效地将胶质瘤细胞U87转分化为神经元,其转 化效率为61.5%。
(4)胶质瘤细胞转分化的神经元的分子表达属性
胶质瘤细胞U251感染慢病毒hNeuroD1-IRES-EGFP和hBrn2-IRES-EGFP 21天后,细胞免疫荧光显 示诱导的神经元表达成熟神经元的标志分子MAP2(图2A)和synapsin I(图2B-D),并且表达谷氨酸能 神经元标志分子VGLUT1(图2E-H),说明诱导的神经元主要是兴奋性神经元。
(5)胶质瘤细胞转分化的神经元的电生理属性
胶质瘤细胞U251感染慢病毒hNeuroD1-IRES-EGFP和hBrn2-IRES-EGFP 28天后,电生理记录显示 诱导神经元能够发放多个动作电位(图3A,B),而且能检测到诱导神经元的突触后电流信号(图3C), 加入阻断剂CNQX和AP5后突触后电流信号消失,说明诱导的神经元能够接受突触信号,是功能性的神 经元。
(6)NeuroD1和Brn2诱导的转分化导致胶质瘤细胞退出细胞周期
神经元细胞是退出细胞周期不再分裂的细胞,NeuroD1和Brn2能将胶质瘤细胞诱导为神经元,会导 致胶质瘤细胞退出细胞周期。为了进一步确证这点,我们在慢病毒感染不同时间段(第1,3,5天)进行BrdU 标记标记2小时,然后进行免疫细胞化学分析(图4A)。与对照组相比,NeuroD1和Brn2慢病毒表达的 胶质瘤细胞BrdU阳性数量比率急剧降低(图4B),提示NeuroD1和Brn2介导的神经元重编程导致神经 胶质瘤细胞退出细胞周期。此外慢病毒感染5天后进行连续的BrdU标记纸质14天,免疫细胞化学分析 表明NeuroD1和Brn2慢病毒表达的胶质瘤细胞BrdU阳性数量明显降低(图4C-E)。
(7)NeuroD1和Brn2诱导的转分化抑制胶质瘤细胞的增殖
进一步我们对作为增殖细胞的内源性分子标记Ki67进行了免疫荧光染色,发现NeuroD1和Brn2慢病 毒表达的胶质瘤细胞Ki67阳性数量明显降低(图5A,B)。我们对病毒感染不同时间后的细胞数目进行 了定量统计,发现感染NeuroD1和Brn2慢病毒的胶质瘤细胞的生长在第7天达到了平稳状态,不再明显 增长(图5C)。
这些结果共同表明,NeuroD1和Brn2可以将恶性增值的胶质瘤细胞诱导为终端分化的神经元,并导致 胶质瘤细胞退出细胞周期,进而不再增殖生长。
(8)表达NeuroD1和Brn2的胶质瘤细胞体内成瘤能力明显降低
由于NeuroD1和Brn2可以将体外培养的胶质瘤细胞诱导为神经元,并导致胶质瘤细胞退出细胞周期, 因此这些诱导的胶质瘤细胞在体内产生肿瘤的能力也将受到影响。我们进行了原位的肿瘤细胞移植实验, 将感染NeuroD1和Brn2慢病毒3天的人胶质瘤细胞U251细胞(5×105)移植到NOD-scid小鼠的纹状体, 21天后评估肿瘤组织体积的大小。结果显示与对照相比,NeuroD1和Brn2慢病毒感染的胶质瘤细胞形成 的肿瘤组织明显更小,说明这些胶质瘤细胞的致瘤能力明显降低。
继而,我们选取转化效率在50%以上的转录因子或转录因子组合我们选取了转化效率在50%以上的 转录因子或转录因子组合,测试了这几组转录因子在胶质瘤细胞中的转分化能力以及对胶质瘤细胞增殖的 抑制能力,发现转分化效率高于75%的转录因子或转录因子组合对胶质细胞来源肿瘤的抑制效果最佳。示 例的优选转录因子及其组合如表9。
表9优选的抑制胶质瘤细胞的转录因子及其组合
实施例6转录因子功能性片段的组合在体内通过重编程抑制脑内胶质瘤细胞的生长
实施例5的基础上,我们尝试在小鼠移植瘤模型上验证转录因子的效果,仍以NeuroD1与Brn2的组 合为例,具体实施如下:
(1)AAV质粒构建
在AAV–FLEX–Arch–GFP(Addgene,#22222)的载体模板上,将源自人NeuroD1(SEQID No.:3)片 段构建到该载体上,得到AAV-hNeuroD1-P2A-GFP。P2A是一种自剪切多肽,实现hNeuroD1和GFP高 效共表达。将源自人Brn2基因的CDS(SEQ ID No.:7)片段构建到该载体上,得到AAV-hBrn2-P2A-GFP。
(2)NeuroD1和Brn2的AAV病毒载体抑制脑内胶质瘤细胞的生长
为了确认NeuroD1和Brn2诱导的重编程是否具有治疗脑胶质瘤细胞的能力,我们先进行了胶质瘤细 胞的脑内移植(5×105)。移植7天后,我们原位注射NeuroD1和Brn2的AAV病毒载体。病毒注射30天 后,免疫组化分析发现感染病毒的细胞表达神经标记分子Tuj1,呈现神经元的形态。以此同时,肿瘤的体 积也明显降低。更重要的是,注射NeuroD1和Brn2的AAV病毒的小鼠生存寿命明显延长。
其他转分化效率高于75%的转录因子或转录因子组合在胶质细胞抑制瘤模型上也观察到了对肿瘤明 显的抑制效果。
实施例7其他递送系统在转录因子功能性片段递送中的应用
除了上述实施例所述的慢病毒载体与腺相关病毒载体,我们还使用来源于间充质细或者胶质母细 胞瘤细胞的外泌体(GBM-Exo)。所述的外泌体从细胞培养的上清液中通过密度梯度离心和分子排阻分离 提取,用Western blot鉴定外泌体标志蛋白CD63的表达,用透射电镜和动态光散射检测外泌体的外形特 征以及粒径,用BCA蛋白定量法检测外泌体浓度。
针对胶质母细胞瘤,通过内源表达或外源导入的方法将Ascl1-mRNA(NCBIReference Sequence: NM_004316.4)或其他本发明所述的转录因子组合导入外泌体中。来源于胶质母细胞瘤的外泌体药物将会 特异感染人胶质母细胞瘤细胞系U251和U87,在细胞对数生长期,可观察到外泌体药物将人胶质母细胞 瘤细胞系U251和U87诱导为神经元的效率可随着外泌体药物的浓度梯度变化,同时相关的肿瘤细胞增殖 的速率也与神经元诱导效率成正比。
以上已对本发明创造的较佳实施例进行了具体说明,但本发明创造并不限于所述的实施例,熟悉本 领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换,这些等同的变型 或替换均包含在本申请权利要求所限定的范围内。
序列表
<110> 再康医药科技(上海)有限公司
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Lys Asn Met Cys Lys Leu Lys Pro Leu Leu Asn Lys Trp Leu Glu Glu
325 330 335
Ala Asp Ser Ser Ser Gly Ser Pro Thr Ser Ile Asp Lys Ile Ala Ala
340 345 350
Gln Gly Arg Lys Arg Lys Lys Arg Thr Ser Ile Glu Val Ser Val Lys
355 360 365
Gly Ala Leu Glu Ser His Phe Leu Lys Cys Pro Lys Pro Ser Ala Gln
370 375 380
Glu Ile Thr Ser Leu Ala Asp Ser Leu Gln Leu Glu Lys Glu Val Val
385 390 395 400
Arg Val Trp Phe Cys Asn Arg Arg Gln Lys Glu Lys Arg Met Thr Pro
405 410 415
Pro Gly Gly Thr Leu Pro Gly Ala Glu Asp Val Tyr Gly Gly Ser Arg
420 425 430
Asp Thr Pro Pro His His Gly Val Gln Thr Pro Val Gln
435 440 445
<210> 7
<211> 1332
<212> DNA
<213> 人
<400> 7
atggcgaccg cagcgtctaa ccactacagc ctgctcacct ccagcgcctc catcgtgcac 60
gccgagccgc ccggcggcat gcagcagggc gcggggggct accgcgaagc gcagagcctg 120
gtgcagggcg actacggcgc tctgcagagc aacggacacc cgctcagcca cgctcaccag 180
tggatcaccg cgctgtccca cggcggcggc ggcgggggcg gtggcggcgg cggggggggc 240
gggggcggcg gcgggggcgg cggcgacggc tccccgtggt ccaccagccc cctgggccag 300
ccggacatca agccctcggt ggtggtgcag cagggcggcc gcggagacga gctgcacggg 360
ccaggcgccc tgcagcagca gcatcagcag cagcaacagc aacagcagca gcaacagcag 420
caacagcagc agcagcagca gcaacagcgg ccgccgcatc tggtgcacca cgccgctaac 480
caccacccgg gacccggggc atggcggagc gcggcggctg cagcgcacct cccaccctcc 540
atgggagcgt ccaacggcgg cttgctctac tcgcagccca gcttcacggt gaacggcatg 600
ctgggcgccg gcgggcagcc ggccggtctg caccaccacg gcctgcggga cgcgcacgac 660
gagccacacc atgccgacca ccacccgcac ccgcactcgc acccacacca gcagccgccg 720
cccccgccgc ccccgcaggg tccgcctggc cacccaggcg cgcaccacga cccgcactcg 780
gacgaggaca cgccgacctc ggacgacctg gagcagttcg ccaagcagtt caagcagcgg 840
cggatcaaac tgggatttac ccaagcggac gtggggctgg ctctgggcac cctgtatggc 900
aacgtgttct cgcagaccac catctgcagg tttgaggccc tgcagctgag cttcaagaac 960
atgtgcaagc tgaagccttt gttgaacaag tggttggagg aggcggactc gtcctcgggc 1020
agccccacga gcatagacaa gatcgcagcg caagggcgca agcggaaaaa gcggacctcc 1080
atcgaggtga gcgtcaaggg ggctctggag agccatttcc tcaaatgccc caagccctcg 1140
gcccaggaga tcacctccct cgcggacagc ttacagctgg agaaggaggt ggtgagagtt 1200
tggttttgta acaggagaca gaaagagaaa aggatgaccc ctcccggagg gactctgccg 1260
ggcgccgagg atgtgtacgg ggggagtagg gacactccac cacaccacgg ggtgcagacg 1320
cccgtccagt ga 1332
<210> 8
<211> 1338
<212> DNA
<213> 小鼠
<400> 8
atggcgaccg cagcgtctaa ccactacagc ctgctcacct ccagcgcctc catcgtacat 60
gccgagccgc ctggcggcat gcagcagggc gcagggggct accgcgaggc gcagagcctg 120
gtgcagggcg actacggcgc gctgcagagc aacgggcacc cgctcagcca cgctcaccag 180
tggatcaccg cgctgtccca cggcggcggc ggcgggggcg gcggcggcgg tggaggaggc 240
gggggaggcg gcgggggagg cggcgacggc tccccgtggt ccaccagccc cctaggccag 300
ccggacatca agccctcggt ggtggtacag cagggtggcc gaggcgacga gctgcacggg 360
ccaggagcgc tgcagcaaca gcatcaacag caacagcaac agcagcagca gcagcagcag 420
cagcagcagc agcaacagca gcagcaacaa cagcgaccgc cacatctggt gcaccacgct 480
gccaaccacc atcccgggcc cggggcatgg cggagtgcgg cggctgcagc tcacctccct 540
ccctccatgg gagcttccaa cggcggtttg ctctattcgc agccgagctt cacggtgaac 600
ggcatgctgg gcgcaggagg gcagccggct gggctgcacc accacggcct gagggacgcc 660
cacgatgagc cacaccatgc agaccaccac ccgcatccgc actctcaccc acaccagcaa 720
ccgcccccgc cacctccccc acaaggccca ccgggccacc caggcgcgca ccacgacccg 780
cactcggacg aggacacgcc gacctcagac gacctggagc agttcgccaa gcaattcaag 840
cagaggcgga tcaaactcgg atttactcaa gcagacgtgg ggctggcgct tggcaccctg 900
tacggcaacg tgttctcgca gaccaccatc tgcaggtttg aggccctgca gctgagcttc 960
aagaacatgt gcaagctgaa gcctttgttg aacaagtggt tggaagaggc agactcatcc 1020
tcgggcagcc ccaccagcat agacaagatc gcagcgcaag ggcgcaaacg gaaaaagcgg 1080
acctccatcg aggtgagcgt caagggggct ctggagagcc atttcctcaa atgccctaag 1140
ccctcggccc aggagatcac ctccctcgcg gacagcttac agctggagaa ggaggtggtg 1200
agagtttggt tttgtaacag gagacagaaa gagaaaagga tgacccctcc cggagggact 1260
ctgccgggcg ccgaggatgt gtatgggggt agtagggaca cgccaccaca ccacggggtg 1320
cagacgcccg tccagtga 1338
<210> 9
<211> 236
<212> PRT
<213> 人
<400> 9
Met Glu Ser Ser Ala Lys Met Glu Ser Gly Gly Ala Gly Gln Gln Pro
1 5 10 15
Gln Pro Gln Pro Gln Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe
20 25 30
Ala Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln
35 40 45
Ser Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ala Pro
50 55 60
Gln Leu Arg Pro Ala Ala Asp Gly Gln Pro Ser Gly Gly Gly His Lys
65 70 75 80
Ser Ala Pro Lys Gln Val Lys Arg Gln Arg Ser Ser Ser Pro Glu Leu
85 90 95
Met Arg Cys Lys Arg Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu
100 105 110
Pro Gln Gln Gln Pro Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg
115 120 125
Asn Arg Val Lys Leu Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His
130 135 140
Val Pro Asn Gly Ala Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu
145 150 155 160
Arg Ser Ala Val Glu Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu
165 170 175
His Asp Ala Val Ser Ala Ala Phe Gln Ala Gly Val Leu Ser Pro Thr
180 185 190
Ile Ser Pro Asn Tyr Ser Asn Asp Leu Asn Ser Met Ala Gly Ser Pro
195 200 205
Val Ser Ser Tyr Ser Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ser Pro
210 215 220
Glu Glu Gln Glu Leu Leu Asp Phe Thr Asn Trp Phe
225 230 235
<210> 10
<211> 231
<212> PRT
<213> 小鼠
<400> 10
Met Glu Ser Ser Gly Lys Met Glu Ser Gly Ala Gly Gln Gln Pro Gln
1 5 10 15
Pro Pro Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe Ala Thr Ala
20 25 30
Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln Ser Ala Gln Gln
35 40 45
Gln Gln Pro Gln Ala Pro Pro Gln Gln Ala Pro Gln Leu Ser Pro Val
50 55 60
Ala Asp Ser Gln Pro Ser Gly Gly Gly His Lys Ser Ala Ala Lys Gln
65 70 75 80
Val Lys Arg Gln Arg Ser Ser Ser Pro Glu Leu Met Arg Cys Lys Arg
85 90 95
Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu Pro Gln Gln Gln Pro
100 105 110
Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg Asn Arg Val Lys Leu
115 120 125
Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His Val Pro Asn Gly Ala
130 135 140
Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu Arg Ser Ala Val Glu
145 150 155 160
Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu His Asp Ala Val Ser
165 170 175
Ala Ala Phe Gln Ala Gly Val Leu Ser Pro Thr Ile Ser Pro Asn Tyr
180 185 190
Ser Asn Asp Leu Asn Ser Met Ala Gly Ser Pro Val Ser Ser Tyr Ser
195 200 205
Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ser Pro Glu Glu Gln Glu Leu
210 215 220
Leu Asp Phe Thr Asn Trp Phe
225 230
<210> 11
<211> 711
<212> DNA
<213> 人
<400> 11
atggaaagct ctgccaagat ggagagcggc ggcgccggcc agcagcccca gccgcagccc 60
cagcagccct tcctgccgcc cgcagcctgt ttctttgcca cggccgcagc cgcggcggcc 120
gcagccgccg cagcggcagc gcagagcgcg cagcagcagc agcagcagca gcagcagcag 180
cagcaggcgc cgcagctgag accggcggcc gacggccagc cctcaggggg cggtcacaag 240
tcagcgccca agcaagtcaa gcgacagcgc tcgtcttcgc ccgaactgat gcgctgcaaa 300
cgccggctca acttcagcgg ctttggctac agcctgccgc agcagcagcc ggccgccgtg 360
gcgcgccgca acgagcgcga gcgcaaccgc gtcaagttgg tcaacctggg ctttgccacc 420
cttcgggagc acgtccccaa cggcgcggcc aacaagaaga tgagtaaggt ggagacactg 480
cgctcggcgg tcgagtacat ccgcgcgctg cagcagctgc tggacgagca tgacgcggtg 540
agcgccgcct tccaggcagg cgtcctgtcg cccaccatct cccccaacta ctccaacgac 600
ttgaactcca tggccggctc gccggtctca tcctactcgt cggacgaggg ctcttacgac 660
ccgctcagcc ccgaggagca ggagcttctc gacttcacca actggttctg a 711
<210> 12
<211> 696
<212> DNA
<213> 小鼠
<400> 12
atggagagct ctggcaagat ggagagtgga gccggccagc agccgcagcc cccgcagccc 60
ttcctgcctc ccgcagcctg cttctttgcg accgcggcgg cggcggcagc ggcggcggcc 120
gcggcagctc agagcgcgca gcagcaacag ccgcaggcgc cgccgcagca ggcgccgcag 180
ctgagcccgg tggccgacag ccagccctca gggggcggtc acaagtcagc ggccaagcag 240
gtcaagcgcc agcgctcgtc ctctccggaa ctgatgcgct gcaaacgccg gctcaacttc 300
agcggcttcg gctacagcct gccacagcag cagccggccg ccgtggcgcg ccgcaacgag 360
cgcgagcgca accgggtcaa gttggtcaac ctgggttttg ccaccctccg ggagcatgtc 420
cccaacggcg cggccaacaa gaagatgagc aaggtggaga cgctgcgctc ggcggtcgag 480
tacatccgcg cgctgcagca gctgctggac gagcacgacg cggtgagcgc tgcctttcag 540
gcgggcgtcc tgtcgcccac catctccccc aactactcca acgacttgaa ctctatggcg 600
ggttctccgg tctcgtccta ctcctccgac gagggatcct acgaccctct tagcccagag 660
gaacaagagc tgctggactt taccaactgg ttctga 696
<210> 13
<211> 272
<212> PRT
<213> 人
<400> 13
Met Phe Val Lys Ser Glu Thr Leu Glu Leu Lys Glu Glu Glu Asp Val
1 5 10 15
Leu Val Leu Leu Gly Ser Ala Ser Pro Ala Leu Ala Ala Leu Thr Pro
20 25 30
Leu Ser Ser Ser Ala Asp Glu Glu Glu Glu Glu Glu Pro Gly Ala Ser
35 40 45
Gly Gly Ala Arg Arg Gln Arg Gly Ala Glu Ala Gly Gln Gly Ala Arg
50 55 60
Gly Gly Val Ala Ala Gly Ala Glu Gly Cys Arg Pro Ala Arg Leu Leu
65 70 75 80
Gly Leu Val His Asp Cys Lys Arg Arg Pro Ser Arg Ala Arg Ala Val
85 90 95
Ser Arg Gly Ala Lys Thr Ala Glu Thr Val Gln Arg Ile Lys Lys Thr
100 105 110
Arg Arg Leu Lys Ala Asn Asn Arg Glu Arg Asn Arg Met His Asn Leu
115 120 125
Asn Ala Ala Leu Asp Ala Leu Arg Glu Val Leu Pro Thr Phe Pro Glu
130 135 140
Asp Ala Lys Leu Thr Lys Ile Glu Thr Leu Arg Phe Ala His Asn Tyr
145 150 155 160
Ile Trp Ala Leu Thr Glu Thr Leu Arg Leu Ala Asp His Cys Gly Gly
165 170 175
Gly Gly Gly Gly Leu Pro Gly Ala Leu Phe Ser Glu Ala Val Leu Leu
180 185 190
Ser Pro Gly Gly Ala Ser Ala Ala Leu Ser Ser Ser Gly Asp Ser Pro
195 200 205
Ser Pro Ala Ser Thr Trp Ser Cys Thr Asn Ser Pro Ala Pro Ser Ser
210 215 220
Ser Val Ser Ser Asn Ser Thr Ser Pro Tyr Ser Cys Thr Leu Ser Pro
225 230 235 240
Ala Ser Pro Ala Gly Ser Asp Met Asp Tyr Trp Gln Pro Pro Pro Pro
245 250 255
Asp Lys His Arg Tyr Ala Pro His Leu Pro Ile Ala Arg Asp Cys Ile
260 265 270
<210> 14
<211> 263
<212> PRT
<213> 小鼠
<400> 14
Met Phe Val Lys Ser Glu Thr Leu Glu Leu Lys Glu Glu Glu Glu Val
1 5 10 15
Leu Met Leu Leu Gly Ser Ala Ser Pro Ala Ser Ala Thr Leu Thr Pro
20 25 30
Met Ser Ser Ser Ala Asp Glu Glu Glu Asp Glu Glu Leu Arg Arg Pro
35 40 45
Gly Ser Ala Arg Gly Gln Arg Gly Ala Glu Ala Gly Gln Gly Val Gln
50 55 60
Gly Ser Pro Ala Ser Gly Ala Gly Gly Cys Arg Pro Gly Arg Leu Leu
65 70 75 80
Gly Leu Met His Glu Cys Lys Arg Arg Pro Ser Arg Ser Arg Ala Val
85 90 95
Ser Arg Gly Ala Lys Thr Ala Glu Thr Val Gln Arg Ile Lys Lys Thr
100 105 110
Arg Arg Leu Lys Ala Asn Asn Arg Glu Arg Asn Arg Met His Asn Leu
115 120 125
Asn Ala Ala Leu Asp Ala Leu Arg Glu Val Leu Pro Thr Phe Pro Glu
130 135 140
Asp Ala Lys Leu Thr Lys Ile Glu Thr Leu Arg Phe Ala His Asn Tyr
145 150 155 160
Ile Trp Ala Leu Thr Glu Thr Leu Arg Leu Ala Asp His Cys Ala Gly
165 170 175
Ala Gly Gly Leu Gln Gly Ala Leu Phe Thr Glu Ala Val Leu Leu Ser
180 185 190
Pro Gly Ala Ala Leu Gly Ala Ser Gly Asp Ser Pro Ser Pro Pro Ser
195 200 205
Ser Trp Ser Cys Thr Asn Ser Pro Ala Ser Ser Ser Asn Ser Thr Ser
210 215 220
Pro Tyr Ser Cys Thr Leu Ser Pro Ala Ser Pro Gly Ser Asp Val Asp
225 230 235 240
Tyr Trp Gln Pro Pro Pro Pro Glu Lys His Arg Tyr Ala Pro His Leu
245 250 255
Pro Leu Ala Arg Asp Cys Ile
260
<210> 15
<211> 819
<212> DNA
<213> 人
<400> 15
atgttcgtca aatccgagac cttggagttg aaggaggaag aggacgtgtt agtgctgctc 60
ggatcggcct cccccgcctt ggcggccctg accccgctgt catccagcgc cgacgaagaa 120
gaggaggagg agccgggcgc gtcaggcggg gcgcgtcggc agcgcggggc tgaggccggg 180
cagggggcgc ggggcggcgt ggctgcgggt gcggagggct gccggcccgc acggctgctg 240
ggtctggtac acgattgcaa acggcgccct tcccgggcgc gggccgtctc ccgaggcgcc 300
aagacggccg agacggtgca gcgcatcaag aagacccgta gactgaaggc caacaaccgc 360
gagcgaaacc gcatgcacaa cctcaacgcg gcactggacg cgctgcgcga ggtgctcccc 420
acgttccccg aggacgccaa gctcaccaag atcgagaccc tgcgcttcgc ccacaactac 480
atctgggcac tcaccgagac cctgcgcctg gcggatcact gcgggggcgg cggcgggggc 540
ctgccggggg cgctcttctc cgaggcagtg ttgctgagcc cgggaggagc cagcgccgcc 600
ctgagcagca gcggagacag cccctcgccc gcctccacgt ggagttgcac caacagcccc 660
gcgccgtcct cctccgtgtc ctccaattcc acctccccct acagctgcac tttatcgccc 720
gccagcccgg ccgggtcaga catggactat tggcagcccc cacctcccga caagcaccgc 780
tatgcacctc acctccccat agccagggat tgtatctag 819
<210> 16
<211> 792
<212> DNA
<213> 小鼠
<400> 16
atgttcgtca aatctgagac tctggagttg aaggaggaag aggaggtact gatgctgctg 60
ggctcggctt ccccggcctc ggcgaccctg accccgatgt cctccagcgc ggacgaggag 120
gaggacgagg agctgcgccg gccgggctcc gcgcgtgggc agcgtggagc ggaagccggg 180
cagggggtgc agggcagtcc ggcgtcgggt gccgggggtt gccggccagg gcggctgctg 240
ggcctgatgc acgagtgcaa gcgtcgcccg tcgcgctcac gggccgtctc ccgaggtgcc 300
aagacggcgg agacggtgca gcgcatcaag aagacccgca ggctcaaggc caacaaccgc 360
gagcgcaacc gcatgcacaa cctaaacgcc gcgctggacg cgctgcgcga ggtgctgccc 420
accttccccg aggatgccaa gctcacgaag atcgagacgc tgcgcttcgc ccacaattac 480
atctgggcgc tcaccgagac tctgcgcctg gcggaccact gcgccggcgc cggtggcctc 540
cagggggcgc tcttcacgga ggcggtgctc ctgagcccgg gagctgcgct cggcgccagc 600
ggggacagcc cttctccacc ttcctcctgg agctgcacca acagcccggc gtcatcctcc 660
aactccacgt ccccatacag ctgcacttta tcgcccgcta gccccgggtc agacgtggac 720
tactggcagc ccccacctcc ggagaagcat cgttatgcgc ctcacctgcc cctcgccagg 780
gactgtatct ag 792
<210> 17
<211> 264
<212> PRT
<213> 人
<400> 17
Met Pro Arg Ser Phe Leu Val Asp Ser Leu Val Leu Arg Glu Ala Gly
1 5 10 15
Glu Lys Lys Ala Pro Glu Gly Ser Pro Pro Pro Leu Phe Pro Tyr Ala
20 25 30
Val Pro Pro Pro His Ala Leu His Gly Leu Ser Pro Gly Ala Cys His
35 40 45
Ala Arg Lys Ala Gly Leu Leu Cys Val Cys Pro Leu Cys Val Thr Ala
50 55 60
Ser Gln Leu His Gly Pro Pro Gly Pro Pro Ala Leu Pro Leu Leu Lys
65 70 75 80
Ala Ser Phe Pro Pro Phe Gly Ser Gln Tyr Cys His Ala Pro Leu Gly
85 90 95
Arg Gln His Ser Ala Val Ser Pro Gly Val Ala His Gly Pro Ala Ala
100 105 110
Ala Ala Ala Ala Ala Ala Leu Tyr Gln Thr Ser Tyr Pro Leu Pro Asp
115 120 125
Pro Arg Gln Phe His Cys Ile Ser Val Asp Ser Ser Ser Asn Gln Leu
130 135 140
Pro Ser Ser Lys Arg Met Arg Thr Ala Phe Thr Ser Thr Gln Leu Leu
145 150 155 160
Glu Leu Glu Arg Glu Phe Ala Ser Asn Met Tyr Leu Ser Arg Leu Arg
165 170 175
Arg Ile Glu Ile Ala Thr Tyr Leu Asn Leu Ser Glu Lys Gln Val Lys
180 185 190
Ile Trp Phe Gln Asn Arg Arg Val Lys His Lys Lys Glu Gly Lys Gly
195 200 205
Ser Asn His Arg Gly Gly Gly Gly Gly Gly Ala Gly Gly Gly Gly Ser
210 215 220
Ala Pro Gln Gly Cys Lys Cys Ala Ser Leu Ser Ser Ala Lys Cys Ser
225 230 235 240
Glu Asp Asp Asp Glu Leu Pro Met Ser Pro Ser Ser Ser Gly Lys Asp
245 250 255
Asp Arg Asp Leu Thr Val Thr Pro
260
<210> 18
<211> 261
<212> PRT
<213> 小鼠
<400> 18
Met Pro Arg Ser Phe Leu Val Asp Ser Leu Val Leu Arg Glu Ala Ser
1 5 10 15
Asp Lys Lys Ala Pro Glu Gly Ser Pro Pro Pro Leu Phe Pro Tyr Ala
20 25 30
Val Pro Pro Pro His Ala Leu His Gly Leu Ser Pro Gly Ala Cys His
35 40 45
Ala Arg Lys Ala Gly Leu Leu Cys Val Cys Pro Leu Cys Val Thr Ala
50 55 60
Ser Gln Leu His Gly Pro Pro Gly Pro Pro Ala Leu Pro Leu Leu Lys
65 70 75 80
Ala Ser Phe Pro Pro Phe Gly Ser Gln Tyr Cys His Ala Pro Leu Gly
85 90 95
Arg Gln His Ser Val Ser Pro Gly Val Ala His Gly Pro Ala Ala Ala
100 105 110
Ala Ala Ala Ala Ala Leu Tyr Gln Thr Ser Tyr Pro Leu Pro Asp Pro
115 120 125
Arg Gln Phe His Cys Ile Ser Val Asp Ser Ser Ser Asn Gln Leu Pro
130 135 140
Ser Ser Lys Arg Met Arg Thr Ala Phe Thr Ser Thr Gln Leu Leu Glu
145 150 155 160
Leu Glu Arg Glu Phe Ala Ser Asn Met Tyr Leu Ser Arg Leu Arg Arg
165 170 175
Ile Glu Ile Ala Thr Tyr Leu Asn Leu Ser Glu Lys Gln Val Lys Ile
180 185 190
Trp Phe Gln Asn Arg Arg Val Lys His Lys Lys Glu Gly Lys Gly Ser
195 200 205
Asn His Arg Gly Gly Ala Gly Ala Gly Ala Gly Gly Gly Ala Pro Gln
210 215 220
Gly Cys Lys Cys Ser Ser Leu Ser Ser Ala Lys Cys Ser Glu Asp Asp
225 230 235 240
Asp Glu Leu Pro Met Ser Pro Ser Ser Ser Gly Lys Asp Asp Arg Asp
245 250 255
Leu Thr Val Thr Pro
260
<210> 19
<211> 795
<212> DNA
<213> 人
<400> 19
atgccgcgct ccttcctggt ggactcgcta gtgctgcgcg aggcgggcga gaagaaggcg 60
cccgagggca gcccgccgcc gctcttcccc tacgctgtgc ccccgccgca cgcgctgcac 120
ggtctctcgc ctggcgcctg ccacgcgcgc aaggctgggc tgctgtgcgt gtgcccgctc 180
tgcgtcaccg cctcgcagct gcatgggccc cccgggccgc ccgcgctgcc tctactcaag 240
gcttccttcc cacccttcgg ctcgcagtac tgccacgcgc ccctgggccg ccagcactct 300
gctgtgtcgc ccggggtcgc tcacggcccg gccgccgctg ctgctgccgc cgcgctctac 360
cagacctcct acccgctgcc tgaccccagg cagttccact gcatctctgt ggacagcagc 420
tctaaccagc tgcccagcag caagaggatg cgcacggctt tcaccagcac gcagctgcta 480
gagctggagc gcgagttcgc ttctaatatg tacctgtccc gcctacgtcg catcgagatc 540
gcgacctacc tgaatctgtc cgagaagcag gtgaagatct ggtttcagaa ccgccgagtg 600
aagcacaaga aggagggcaa gggcagcaac catcgtggcg gcggcggcgg gggtgccggt 660
ggtggcggga gcgcaccgca aggctgcaag tgcgcatcgc tctcctcagc caagtgctcc 720
gaggatgacg acgaattgcc catgtctccg tcctcctcag ggaaggacga ccgggatctt 780
acggtcactc cctag 795
<210> 20
<211> 786
<212> DNA
<213> 小鼠
<400> 20
atgccgcgct ccttcctggt ggattccctt gtgctgcggg aagccagcga caagaaggct 60
ccggagggca gcccgccacc gctcttcccc tacgcggtcc cgccgccgca cgcgctccac 120
ggcctctcgc cgggcgcctg ccacgcgcgc aaggccggct tgctgtgcgt gtgtcccctc 180
tgtgtcaccg cttcgcagct gcacgggccc cccgggccgc cggcactgcc gctactcaag 240
gcgtccttcc ctcccttcgg atcgcagtac tgccacgcac ccctgggccg ccagcactcc 300
gtgtcccctg gagtcgccca cggcccggct gcggccgcag cagctgctgc actctaccag 360
acctcctacc cgctgccgga tcccagacag tttcactgca tctctgtgga cagcagctcg 420
aaccagctgc ccagcagcaa gaggatgcgg acggcgttca ccagcacaca gctcctggag 480
ctggagcgag agttcgcctc caacatgtac ctctcccgcc tgcggcgcat cgagatcgcg 540
acctatctga acctgtccga gaagcaggtg aagatctggt ttcagaaccg ccgggtgaag 600
cacaagaaag aaggcaaagg cagtaaccac cgcggcggag ctggggcggg ggccggcggg 660
ggcgcaccgc aaggctgcaa gtgctcttcg ctctcctcag ccaaatgctc agaggacgac 720
gacgaattgc ccatgtctcc atcttcctcc gggaaggatg acagagatct cacagtcact 780
ccgtag 786
<210> 21
<211> 682
<212> PRT
<213> 人
<400> 21
Met Gln Leu Glu His Cys Leu Ser Pro Ser Ile Met Leu Ser Lys Lys
1 5 10 15
Phe Leu Asn Val Ser Ser Ser Tyr Pro His Ser Gly Gly Ser Glu Leu
20 25 30
Val Leu His Asp His Pro Ile Ile Ser Thr Thr Asp Asn Leu Glu Arg
35 40 45
Ser Ser Pro Leu Lys Lys Ile Thr Arg Gly Met Thr Asn Gln Ser Asp
50 55 60
Thr Asp Asn Phe Pro Asp Ser Lys Asp Ser Pro Gly Asp Val Gln Arg
65 70 75 80
Ser Lys Leu Ser Pro Val Leu Asp Gly Val Ser Glu Leu Arg His Ser
85 90 95
Phe Asp Gly Ser Ala Ala Asp Arg Tyr Leu Leu Ser Gln Ser Ser Gln
100 105 110
Pro Gln Ser Ala Ala Thr Ala Pro Ser Ala Met Phe Pro Tyr Pro Gly
115 120 125
Gln His Gly Pro Ala His Pro Ala Phe Ser Ile Gly Ser Pro Ser Arg
130 135 140
Tyr Met Ala His His Pro Val Ile Thr Asn Gly Ala Tyr Asn Ser Leu
145 150 155 160
Leu Ser Asn Ser Ser Pro Gln Gly Tyr Pro Thr Ala Gly Tyr Pro Tyr
165 170 175
Pro Gln Gln Tyr Gly His Ser Tyr Gln Gly Ala Pro Phe Tyr Gln Phe
180 185 190
Ser Ser Thr Gln Pro Gly Leu Val Pro Gly Lys Ala Gln Val Tyr Leu
195 200 205
Cys Asn Arg Pro Leu Trp Leu Lys Phe His Arg His Gln Thr Glu Met
210 215 220
Ile Ile Thr Lys Gln Gly Arg Arg Met Phe Pro Phe Leu Ser Phe Asn
225 230 235 240
Ile Ser Gly Leu Asp Pro Thr Ala His Tyr Asn Ile Phe Val Asp Val
245 250 255
Ile Leu Ala Asp Pro Asn His Trp Arg Phe Gln Gly Gly Lys Trp Val
260 265 270
Pro Cys Gly Lys Ala Asp Thr Asn Val Gln Gly Asn Arg Val Tyr Met
275 280 285
His Pro Asp Ser Pro Asn Thr Gly Ala His Trp Met Arg Gln Glu Ile
290 295 300
Ser Phe Gly Lys Leu Lys Leu Thr Asn Asn Lys Gly Ala Ser Asn Asn
305 310 315 320
Asn Gly Gln Met Val Val Leu Gln Ser Leu His Lys Tyr Gln Pro Arg
325 330 335
Leu His Val Val Glu Val Asn Glu Asp Gly Thr Glu Asp Thr Ser Gln
340 345 350
Pro Gly Arg Val Gln Thr Phe Thr Phe Pro Glu Thr Gln Phe Ile Ala
355 360 365
Val Thr Ala Tyr Gln Asn Thr Asp Ile Thr Gln Leu Lys Ile Asp His
370 375 380
Asn Pro Phe Ala Lys Gly Phe Arg Asp Asn Tyr Asp Thr Ile Tyr Thr
385 390 395 400
Gly Cys Asp Met Asp Arg Leu Thr Pro Ser Pro Asn Asp Ser Pro Arg
405 410 415
Ser Gln Ile Val Pro Gly Ala Arg Tyr Ala Met Ala Gly Ser Phe Leu
420 425 430
Gln Asp Gln Phe Val Ser Asn Tyr Ala Lys Ala Arg Phe His Pro Gly
435 440 445
Ala Gly Ala Gly Pro Gly Pro Gly Thr Asp Arg Ser Val Pro His Thr
450 455 460
Asn Gly Leu Leu Ser Pro Gln Gln Ala Glu Asp Pro Gly Ala Pro Ser
465 470 475 480
Pro Gln Arg Trp Phe Val Thr Pro Ala Asn Asn Arg Leu Asp Phe Ala
485 490 495
Ala Ser Ala Tyr Asp Thr Ala Thr Asp Phe Ala Gly Asn Ala Ala Thr
500 505 510
Leu Leu Ser Tyr Ala Ala Ala Gly Val Lys Ala Leu Pro Leu Gln Ala
515 520 525
Ala Gly Cys Thr Gly Arg Pro Leu Gly Tyr Tyr Ala Asp Pro Ser Gly
530 535 540
Trp Gly Ala Arg Ser Pro Pro Gln Tyr Cys Gly Thr Lys Ser Gly Ser
545 550 555 560
Val Leu Pro Cys Trp Pro Asn Ser Ala Ala Ala Ala Ala Arg Met Ala
565 570 575
Gly Ala Asn Pro Tyr Leu Gly Glu Glu Ala Glu Gly Leu Ala Ala Glu
580 585 590
Arg Ser Pro Leu Pro Pro Gly Ala Ala Glu Asp Ala Lys Pro Lys Asp
595 600 605
Leu Ser Asp Ser Ser Trp Ile Glu Thr Pro Ser Ser Ile Lys Ser Ile
610 615 620
Asp Ser Ser Asp Ser Gly Ile Tyr Glu Gln Ala Lys Arg Arg Arg Ile
625 630 635 640
Ser Pro Ala Asp Thr Pro Val Ser Glu Ser Ser Ser Pro Leu Lys Ser
645 650 655
Glu Val Leu Ala Gln Arg Asp Cys Glu Lys Asn Cys Ala Lys Asp Ile
660 665 670
Ser Gly Tyr Tyr Gly Phe Tyr Ser His Ser
675 680
<210> 22
<211> 681
<212> PRT
<213> 小鼠
<400> 22
Met Gln Leu Glu His Cys Leu Ser Pro Ser Ile Met Leu Ser Lys Lys
1 5 10 15
Phe Leu Asn Val Ser Ser Ser Tyr Pro His Ser Gly Gly Ser Glu Leu
20 25 30
Val Leu His Asp His Pro Ile Ile Ser Thr Thr Asp Asn Leu Glu Arg
35 40 45
Ser Ser Pro Leu Lys Lys Ile Thr Arg Gly Met Thr Asn Gln Ser Asp
50 55 60
Thr Asp Asn Phe Pro Asp Ser Lys Asp Ser Pro Gly Asp Val Gln Arg
65 70 75 80
Ser Lys Leu Ser Pro Val Leu Asp Gly Val Ser Glu Leu Arg His Ser
85 90 95
Phe Asp Gly Ser Ala Ala Asp Arg Tyr Leu Leu Ser Gln Ser Ser Gln
100 105 110
Pro Gln Ser Ala Ala Thr Ala Pro Ser Ala Met Phe Pro Tyr Pro Ser
115 120 125
Gln His Gly Pro Ala His Pro Ala Phe Ser Ile Gly Ser Pro Ser Arg
130 135 140
Tyr Met Ala His His Pro Val Ile Thr Asn Gly Ala Tyr Asn Ser Leu
145 150 155 160
Leu Ser Asn Ser Ser Pro Gln Gly Tyr Pro Thr Ala Gly Tyr Pro Tyr
165 170 175
Pro Gln Gln Tyr Gly His Ser Tyr Gln Gly Ala Pro Phe Tyr Gln Phe
180 185 190
Ser Ser Thr Gln Pro Gly Leu Val Pro Gly Lys Ala Gln Val Tyr Leu
195 200 205
Cys Asn Arg Pro Leu Trp Leu Lys Phe His Arg His Gln Thr Glu Met
210 215 220
Ile Ile Thr Lys Gln Gly Arg Arg Met Phe Pro Phe Leu Ser Phe Asn
225 230 235 240
Ile Ser Gly Leu Asp Pro Thr Ala His Tyr Asn Ile Phe Val Asp Val
245 250 255
Ile Leu Ala Asp Pro Asn His Trp Arg Phe Gln Gly Gly Lys Trp Val
260 265 270
Pro Cys Gly Lys Ala Asp Thr Asn Val Gln Gly Asn Arg Val Tyr Met
275 280 285
His Pro Asp Ser Pro Asn Thr Gly Ala His Trp Met Arg Gln Glu Ile
290 295 300
Ser Phe Gly Lys Leu Lys Leu Thr Asn Asn Lys Gly Ala Ser Asn Asn
305 310 315 320
Asn Gly Gln Met Val Val Leu Gln Ser Leu His Lys Tyr Gln Pro Arg
325 330 335
Leu His Val Val Glu Val Asn Glu Asp Gly Thr Glu Asp Thr Ser Gln
340 345 350
Pro Gly Arg Val Gln Thr Phe Thr Phe Pro Glu Thr Gln Phe Ile Ala
355 360 365
Val Thr Ala Tyr Gln Asn Thr Asp Ile Thr Gln Leu Lys Ile Asp His
370 375 380
Asn Pro Phe Ala Lys Gly Phe Arg Asp Asn Tyr Asp Thr Ile Tyr Thr
385 390 395 400
Gly Cys Asp Met Asp Arg Leu Thr Pro Ser Pro Asn Asp Ser Pro Arg
405 410 415
Ser Gln Ile Val Pro Gly Ala Arg Tyr Ala Met Ala Gly Ser Phe Leu
420 425 430
Gln Asp Gln Phe Val Ser Asn Tyr Ala Lys Ala Arg Phe His Pro Gly
435 440 445
Ala Gly Ala Gly Pro Gly Pro Gly Thr Asp Arg Ser Val Pro His Thr
450 455 460
Asn Gly Leu Leu Ser Pro Gln Gln Ala Glu Asp Pro Gly Ala Pro Ser
465 470 475 480
Pro Gln Arg Trp Phe Val Thr Pro Ala Asn Asn Arg Leu Asp Phe Ala
485 490 495
Ala Ser Ala Tyr Asp Thr Ala Thr Asp Phe Ala Gly Asn Ala Ala Thr
500 505 510
Leu Leu Ser Tyr Ala Ala Ala Gly Val Lys Ala Leu Pro Leu Gln Ala
515 520 525
Ala Gly Cys Thr Gly Arg Pro Leu Gly Tyr Tyr Ala Asp Pro Ser Gly
530 535 540
Trp Gly Ala Arg Ser Pro Pro Gln Tyr Cys Gly Ala Lys Ser Gly Ser
545 550 555 560
Val Leu Pro Cys Trp Pro Asn Ser Ala Ala Ala Ala Ala Arg Met Ala
565 570 575
Gly Ala Asn Pro Tyr Leu Gly Glu Glu Ala Glu Gly Leu Ala Ala Glu
580 585 590
Arg Ser Pro Leu Ala Pro Ala Ala Glu Asp Ala Lys Pro Lys Asp Leu
595 600 605
Ser Asp Ser Ser Trp Ile Glu Thr Pro Ser Ser Ile Lys Ser Ile Asp
610 615 620
Ser Ser Asp Ser Gly Ile Tyr Glu Gln Ala Lys Arg Arg Arg Ile Ser
625 630 635 640
Pro Ala Asp Thr Pro Val Ser Glu Ser Ser Ser Pro Leu Lys Ser Glu
645 650 655
Val Leu Ala Gln Arg Asp Cys Glu Lys Asn Cys Ala Lys Asp Ile Gly
660 665 670
Gly Tyr Tyr Gly Phe Tyr Ser His Ser
675 680
<210> 23
<211> 2049
<212> DNA
<213> 人
<400> 23
atgcagctgg agcactgcct ttctccttct atcatgctct ccaagaaatt tctcaatgtg 60
agcagcagct acccacattc aggcggatcc gagcttgtct tgcacgatca tcccattatc 120
tcgaccactg acaacctgga gagaagttca cctttgaaaa aaattaccag ggggatgacg 180
aatcagtcag atacagacaa ttttcctgac tccaaggact caccagggga cgtccagaga 240
agtaaactct ctcctgtctt ggacggggtc tctgagcttc gtcacagttt cgatggctct 300
gctgcagatc gctacctcct ctctcagtcc agccagccac agtctgcggc cactgctccc 360
agtgccatgt tcccgtaccc cggccagcac ggaccggcgc accccgcctt ctccatcggc 420
agccctagcc gctacatggc ccaccacccg gtcatcacca acggagccta caacagcctc 480
ctgtccaact cctcgccgca gggatacccc acggccggct acccctaccc acagcagtac 540
ggccactcct accaaggagc tccgttctac cagttctcct ccacccagcc ggggctggtg 600
cccggcaaag cacaggtgta cctgtgcaac aggccccttt ggctgaaatt tcaccggcac 660
caaacggaga tgatcatcac caaacaggga aggcgcatgt ttcctttttt aagttttaac 720
atttctggtc tcgatcccac ggctcattac aatatttttg tggatgtgat tttggcggat 780
cccaatcact ggaggtttca aggaggcaaa tgggttcctt gcggcaaagc ggacaccaat 840
gtgcaaggaa atcgggtcta tatgcatccg gattccccca acactggggc tcactggatg 900
cgccaagaaa tctcttttgg aaaattaaaa cttacgaaca acaaaggagc ttcaaataac 960
aatgggcaga tggtggtttt acagtccttg cacaagtacc agccccgcct gcatgtggtg 1020
gaagtgaacg aggacggcac ggaggacact agccagcccg gccgcgtgca gacgttcact 1080
ttccctgaga ctcagttcat cgccgtcacc gcctaccaga acacggatat tacacaactg 1140
aaaatagatc acaacccttt tgcaaaagga tttcgggata attatgacac gatctacacc 1200
ggctgtgaca tggaccgcct gaccccctcg cccaacgact cgccgcgctc gcagatcgtg 1260
cccggggccc gctacgccat ggccggctct ttcctgcagg accagttcgt gagcaactac 1320
gccaaggccc gcttccaccc gggcgcgggc gcgggccccg ggccgggtac ggaccgcagc 1380
gtgccgcaca ccaacgggct gctgtcgccg cagcaggccg aggacccggg cgcgccctcg 1440
ccgcaacgct ggtttgtgac gccggccaac aaccggctgg acttcgcggc ctcggcctat 1500
gacacggcca cggacttcgc gggcaacgcg gccacgctgc tctcttacgc ggcggcgggc 1560
gtgaaggcgc tgccgctgca ggctgcaggc tgcactggcc gcccgctcgg ctactacgcc 1620
gacccgtcgg gctggggcgc ccgcagtccc ccgcagtact gcggcaccaa gtcgggctcg 1680
gtgctgccct gctggcccaa cagcgccgcg gccgccgcgc gcatggccgg cgccaatccc 1740
tacctgggcg aggaggccga gggcctggcc gccgagcgct cgccgctgcc gcccggcgcc 1800
gccgaggacg ccaagcccaa ggacctgtcc gattccagct ggatcgagac gccctcctcg 1860
atcaagtcca tcgactccag cgactcgggg atttacgagc aggccaagcg gaggcggatc 1920
tcgccggccg acacgcccgt gtccgagagt tcgtccccgc tcaagagcga ggtgctggcc 1980
cagcgggact gcgagaagaa ctgcgccaag gacattagcg gctactatgg cttctactcg 2040
cacagctag 2049
<210> 24
<211> 2046
<212> DNA
<213> 小鼠
<400> 24
atgcagctgg agcattgcct ctctccttct atcatgctct ccaagaaatt tctcaatgtg 60
agcagcagct acccacattc gggcggatct gagcttgtct tgcatgatca tcccattatc 120
tcgaccactg acaacctgga gagaagttca cctttgaaaa aaattaccag ggggatgacg 180
aatcagtcag atacagacaa ttttcctgac tccaaggact caccagggga cgtccagaga 240
agtaaactct ctcctgtctt ggacggggtc tctgagcttc gtcacagttt cgatggctct 300
gctgcagatc gttacctact ctctcagtcc agccagccac agtctgcggc caccgctccc 360
agtgccatgt tcccgtaccc cagccagcac ggaccggcgc atcccgcctt ctccatcggc 420
agccccagtc gctacatggc ccaccacccg gtcattacca acggagctta caacagcctg 480
ctgtccaact cttcgccgca gggctacccc acggccggct acccctaccc acagcagtac 540
ggccactcct accaaggagc ccctttctac cagttctcct ccacccagcc cgggttggtg 600
cccggcaagg cgcaagtata cctgtgcaac aggccacttt ggctgaaatt tcatcggcat 660
caaacggaga tgatcatcac taaacaggga aggcgcatgt ttcccttttt gagttttaac 720
atttctggtc tcgatcccac cgctcattac aatatttttg tggatgtgat tttggcggat 780
cccaatcact ggaggtttca aggaggcaaa tgggttcctt gtggcaaagc ggacaccaat 840
gtgcaaggaa accgggtcta tatgcatccg gattccccca acactggggc tcactggatg 900
cggcaagaaa tctcttttgg aaaattaaaa cttaccaaca acaagggagc atcaaacaac 960
aatgggcaga tggtggtttt acagtccctg cacaagtacc agccccgtct gcacgtggtg 1020
gaagtgaatg aggatggcac agaggacacc agccagccag gccgagtcca gacgttcact 1080
tttccggaga ctcagttcat cgctgtcacc gcctaccaga acacggatat tacacaacta 1140
aaaatagatc ataacccctt tgcaaaagga tttcgagata actatgacac gatctacacg 1200
ggctgcgaca tggaccgctt gaccccgtcg cccaacgact ctccgcgctc gcagatcgtg 1260
cccggcgccc gctacgccat ggccggctct ttcctgcaag accagttcgt gagcaactac 1320
gccaaggccc gcttccaccc gggcgccggc gcgggtcccg ggccgggcac ggaccgcagc 1380
gtgccgcaca ccaacgggct gctgtccccg cagcaggccg aggacccggg cgcgccgtcg 1440
ccgcagcgct ggttcgtcac gccggccaac aaccggctgg acttcgcggc ctcggcctac 1500
gacacggcca cggacttcgc cggcaacgcg gccacgctgc tgtcgtatgc ggccgcgggc 1560
gtgaaggcgc tgcccttgca ggccgcgggc tgcacgggcc gcccgctcgg ctactacgcc 1620
gacccttcgg gctggggcgc gcgcagcccc ccgcagtact gcggcgccaa gtcgggctcc 1680
gtgctcccct gctggcccaa cagcgccgcg gccgccgcgc gcatggccgg cgccaacccc 1740
tatctgggcg aggaggccga gggcctggcg gccgagcgct cgccgctggc gcccgccgcc 1800
gaggacgcca agcccaagga cctgtccgac tccagctgga tcgagacgcc ctcctccatc 1860
aaatccatcg actccagcga ctcggggatt tacgagcagg ccaagcggag gcggatctcg 1920
ccggctgaca cgccggtgtc tgagagctcg tccccgctca agagcgaggt gctggcccag 1980
cgggactgcg agaagaactg cgccaaggac ataggcggct actatggctt ctactcgcac 2040
agctag 2046
<210> 25
<211> 328
<212> PRT
<213> 人
<400> 25
Met Thr Gly Val Phe Asp Ser Leu Val Ala Asp Met His Ser Thr Gln
1 5 10 15
Ile Ala Ala Ser Ser Thr Tyr His Gln His Gln Gln Pro Pro Ser Gly
20 25 30
Gly Gly Ala Gly Pro Gly Gly Asn Ser Ser Ser Ser Ser Ser Leu His
35 40 45
Lys Pro Gln Glu Ser Pro Thr Leu Pro Val Ser Thr Ala Thr Asp Ser
50 55 60
Ser Tyr Tyr Thr Asn Gln Gln His Pro Ala Gly Gly Gly Gly Gly Gly
65 70 75 80
Gly Ser Pro Tyr Ala His Met Gly Ser Tyr Gln Tyr Gln Ala Ser Gly
85 90 95
Leu Asn Asn Val Pro Tyr Ser Ala Lys Ser Ser Tyr Asp Leu Gly Tyr
100 105 110
Thr Ala Ala Tyr Thr Ser Tyr Ala Pro Tyr Gly Thr Ser Ser Ser Pro
115 120 125
Ala Asn Asn Glu Pro Glu Lys Glu Asp Leu Glu Pro Glu Ile Arg Ile
130 135 140
Val Asn Gly Lys Pro Lys Lys Val Arg Lys Pro Arg Thr Ile Tyr Ser
145 150 155 160
Ser Phe Gln Leu Ala Ala Leu Gln Arg Arg Phe Gln Lys Thr Gln Tyr
165 170 175
Leu Ala Leu Pro Glu Arg Ala Glu Leu Ala Ala Ser Leu Gly Leu Thr
180 185 190
Gln Thr Gln Val Lys Ile Trp Phe Gln Asn Arg Arg Ser Lys Phe Lys
195 200 205
Lys Met Trp Lys Ser Gly Glu Ile Pro Ser Glu Gln His Pro Gly Ala
210 215 220
Ser Ala Ser Pro Pro Cys Ala Ser Pro Pro Val Ser Ala Pro Ala Ser
225 230 235 240
Trp Asp Phe Gly Val Pro Gln Arg Met Ala Gly Gly Gly Gly Pro Gly
245 250 255
Ser Gly Gly Ser Gly Ala Gly Ser Ser Gly Ser Ser Pro Ser Ser Ala
260 265 270
Ala Ser Ala Phe Leu Gly Asn Tyr Pro Trp Tyr His Gln Thr Ser Gly
275 280 285
Ser Ala Ser His Leu Gln Ala Thr Ala Pro Leu Leu His Pro Thr Gln
290 295 300
Thr Pro Gln Pro His His His His His His His Gly Gly Gly Gly Ala
305 310 315 320
Pro Val Ser Ala Gly Thr Ile Phe
325
<210> 26
<211> 332
<212> PRT
<213> 小鼠
<400> 26
Met Thr Gly Val Phe Asp Ser Leu Val Ala Asp Met His Ser Thr Gln
1 5 10 15
Ile Thr Ala Ser Ser Thr Tyr His Gln His Gln Gln Pro Pro Ser Gly
20 25 30
Ala Gly Ala Gly Pro Gly Gly Asn Ser Asn Ser Ser Ser Ser Asn Ser
35 40 45
Ser Leu His Lys Pro Gln Glu Ser Pro Thr Leu Pro Val Ser Thr Ala
50 55 60
Thr Asp Ser Ser Tyr Tyr Thr Asn Gln Gln His Pro Ala Gly Gly Gly
65 70 75 80
Gly Gly Gly Ala Ser Pro Tyr Ala His Met Gly Ser Tyr Gln Tyr His
85 90 95
Ala Ser Gly Leu Asn Asn Val Ser Tyr Ser Ala Lys Ser Ser Tyr Asp
100 105 110
Leu Gly Tyr Thr Ala Ala Tyr Thr Ser Tyr Ala Pro Tyr Gly Thr Ser
115 120 125
Ser Ser Pro Val Asn Asn Glu Pro Asp Lys Glu Asp Leu Glu Pro Glu
130 135 140
Ile Arg Ile Val Asn Gly Lys Pro Lys Lys Val Arg Lys Pro Arg Thr
145 150 155 160
Ile Tyr Ser Ser Phe Gln Leu Ala Ala Leu Gln Arg Arg Phe Gln Lys
165 170 175
Thr Gln Tyr Leu Ala Leu Pro Glu Arg Ala Glu Leu Ala Ala Ser Leu
180 185 190
Gly Leu Thr Gln Thr Gln Val Lys Ile Trp Phe Gln Asn Arg Arg Ser
195 200 205
Lys Phe Lys Lys Met Trp Lys Ser Gly Glu Ile Pro Thr Glu Gln His
210 215 220
Pro Gly Ala Ser Ala Ser Pro Pro Cys Ala Ser Pro Pro Val Ser Ala
225 230 235 240
Pro Ala Ser Trp Asp Phe Gly Ala Pro Gln Arg Met Ala Gly Gly Gly
245 250 255
Pro Gly Ser Gly Gly Gly Gly Ala Gly Ser Ser Gly Ser Ser Pro Ser
260 265 270
Ser Ala Ala Ser Ala Phe Leu Gly Asn Tyr Pro Trp Tyr His Gln Ala
275 280 285
Ser Gly Ser Ala Ser His Leu Gln Ala Thr Ala Pro Leu Leu His Pro
290 295 300
Ser Gln Thr Pro Gln Ala His His His His His His His His His Ala
305 310 315 320
Gly Gly Gly Ala Pro Val Ser Ala Gly Thr Ile Phe
325 330
<210> 27
<211> 987
<212> DNA
<213> 人
<400> 27
atgactggag tctttgacag tctagtggct gatatgcact cgacccagat cgccgcctcc 60
agcacgtacc accagcacca gcagcccccg agcggcggcg gcgccggccc gggtggcaac 120
agcagcagca gcagcagcct ccacaagccc caggagtcgc ccacccttcc ggtgtccacc 180
gccaccgaca gcagctacta caccaaccag cagcacccgg cgggcggcgg cggcggcggg 240
ggctcgccct acgcgcacat gggttcctac cagtaccaag ccagcggcct caacaacgtc 300
ccttactccg ccaagagcag ctatgacctg ggctacaccg ccgcctacac ctcctacgct 360
ccctatggaa ccagttcgtc cccagccaac aacgagcctg agaaggagga ccttgagcct 420
gaaattcgga tagtgaacgg gaagccaaag aaagtccgga aaccccgcac catctactcc 480
agtttccagc tggcggctct tcagcggcgt ttccaaaaga ctcaatactt ggccttgccg 540
gagcgagccg agctggcggc ctctctgggc ctcacccaga ctcaggtcaa aatctggttc 600
cagaaccgcc ggtccaagtt caagaagatg tggaaaagtg gtgagatccc ctcggagcag 660
caccctgggg ccagcgcttc tccaccttgt gcttcgccgc cagtctcagc gccggcctcc 720
tgggactttg gtgtgccgca gcggatggcg ggcggcggtg gtccgggcag tggcggcagc 780
ggcgccggca gctcgggctc cagcccgagc agcgcggcct cggcttttct gggcaactac 840
ccctggtacc accagacctc gggatccgcc tcacacctgc aggccacggc gccgctgctg 900
caccccactc agaccccgca gccgcatcac caccaccacc atcacggcgg cgggggcgcc 960
ccggtgagcg cggggacgat tttctaa 987
<210> 28
<211> 999
<212> DNA
<213> 小鼠
<400> 28
atgactggag tctttgacag tctggtggct gatatgcact cgacccagat caccgcctcc 60
agcacgtacc accagcacca gcagcccccg agcggtgcgg gcgccggccc tggcggcaac 120
agcaacagca gcagcagcaa cagcagcctg cacaagcccc aggagtcgcc aaccctcccg 180
gtgtccacgg ctacggacag cagctactac accaaccagc agcacccggc gggcggcggc 240
ggcggggggg cctcgcccta cgcgcacatg ggctcctacc agtaccacgc cagcggcctc 300
aacaatgtct cctactccgc caaaagcagc tacgacctgg gctacaccgc cgcgtacacc 360
tcctacgcgc cctacggcac cagttcgtct ccggtcaaca acgagccgga caaggaagac 420
cttgagcctg aaatccgaat agtgaacggg aagccaaaga aagtccggaa accacgcacc 480
atctactcca gtttccagct ggcggccctt caacgacgct tccagaagac ccagtatctg 540
gccctgccag agcgagccga gctggcggcg tccctgggcc tcacccaaac tcaggtcaaa 600
atctggttcc agaaccgccg atccaagttc aagaagatgt ggaaaagcgg cgagataccc 660
accgagcagc accctggagc cagcgcttct cctccttgtg cctccccgcc ggtctcggcg 720
ccagcatcct gggacttcgg cgcgccgcag cggatggctg gcggcggccc gggcagcgga 780
ggcggcggtg cgggcagctc tggctccagc ccgagcagcg ccgcctcggc ctttctggga 840
aactacccgt ggtaccacca ggcttcgggc tccgcttcac acctgcaggc cacagcgcca 900
cttctgcatc cttcgcagac tccgcaggcg caccatcacc accatcacca ccaccacgca 960
ggcgggggcg ccccggtgag cgcggggacg attttctaa 999
<210> 29
<211> 328
<212> PRT
<213> 人
<400> 29
Met Asp Ala Val Leu Leu Glu His Phe Pro Gly Gly Leu Asp Ala Phe
1 5 10 15
Pro Ser Ser Tyr Phe Asp Glu Asp Asp Phe Phe Thr Asp Gln Ser Ser
20 25 30
Arg Asp Pro Leu Glu Asp Gly Asp Glu Leu Leu Ala Asp Glu Gln Ala
35 40 45
Glu Val Glu Phe Leu Ser His Gln Leu His Glu Tyr Cys Tyr Arg Asp
50 55 60
Gly Ala Cys Leu Leu Leu Gln Pro Ala Pro Pro Ala Ala Pro Leu Ala
65 70 75 80
Leu Ala Pro Pro Ser Ser Gly Gly Leu Gly Glu Pro Asp Asp Gly Gly
85 90 95
Gly Gly Gly Tyr Cys Cys Glu Thr Gly Ala Pro Pro Gly Gly Phe Pro
100 105 110
Tyr Ser Pro Gly Ser Pro Pro Ser Cys Leu Ala Tyr Pro Cys Ala Gly
115 120 125
Ala Ala Val Leu Ser Pro Gly Ala Arg Leu Arg Gly Leu Ser Gly Ala
130 135 140
Ala Ala Ala Ala Ala Arg Arg Arg Arg Arg Val Arg Ser Glu Ala Glu
145 150 155 160
Leu Gln Gln Leu Arg Gln Ala Ala Asn Val Arg Glu Arg Arg Arg Met
165 170 175
Gln Ser Ile Asn Asp Ala Phe Glu Gly Leu Arg Ser His Ile Pro Thr
180 185 190
Leu Pro Tyr Glu Lys Arg Leu Ser Lys Val Asp Thr Leu Arg Leu Ala
195 200 205
Ile Gly Tyr Ile Asn Phe Leu Ser Glu Leu Val Gln Ala Asp Leu Pro
210 215 220
Leu Arg Gly Gly Gly Ala Gly Gly Cys Gly Gly Pro Gly Gly Gly Gly
225 230 235 240
Arg Leu Gly Gly Asp Ser Pro Gly Ser Gln Ala Gln Lys Val Ile Ile
245 250 255
Cys His Arg Gly Thr Arg Ser Pro Ser Pro Ser Asp Pro Asp Tyr Gly
260 265 270
Leu Pro Pro Leu Ala Gly His Ser Leu Ser Trp Thr Asp Glu Lys Gln
275 280 285
Leu Lys Glu Gln Asn Ile Ile Arg Thr Ala Lys Val Trp Thr Pro Glu
290 295 300
Asp Pro Arg Lys Leu Asn Ser Lys Ser Ser Phe Asn Asn Ile Glu Asn
305 310 315 320
Glu Pro Pro Phe Glu Phe Val Ser
325
<210> 30
<211> 324
<212> PRT
<213> 小鼠
<400> 30
Met Asp Ala Val Leu Leu Glu His Phe Pro Gly Gly Leu Asp Thr Phe
1 5 10 15
Pro Ser Pro Tyr Phe Asp Glu Glu Asp Phe Phe Thr Asp Gln Ser Ser
20 25 30
Arg Asp Pro Leu Glu Asp Ser Asp Glu Leu Leu Gly Asp Glu Gln Ala
35 40 45
Glu Val Glu Phe Leu Ser His Gln Leu His Glu Tyr Cys Tyr Arg Asp
50 55 60
Gly Ala Cys Leu Leu Leu Gln Pro Ala Pro Ser Ala Ala Pro His Ala
65 70 75 80
Leu Ala Pro Pro Pro Leu Gly Asp Pro Gly Glu Pro Glu Asp Asn Val
85 90 95
Ser Tyr Cys Cys Asp Ala Gly Ala Pro Leu Ala Ala Phe Pro Tyr Ser
100 105 110
Pro Gly Ser Pro Pro Ser Cys Leu Ala Tyr Pro Cys Ala Ala Val Leu
115 120 125
Ser Pro Gly Ala Arg Leu Gly Gly Leu Asn Gly Ala Ala Ala Ala Ala
130 135 140
Ala Ala Arg Arg Arg Arg Arg Val Arg Ser Glu Ala Glu Leu Gln Gln
145 150 155 160
Leu Arg Gln Ala Ala Asn Val Arg Glu Arg Arg Arg Met Gln Ser Ile
165 170 175
Asn Asp Ala Phe Glu Gly Leu Arg Ser His Ile Pro Thr Leu Pro Tyr
180 185 190
Glu Lys Arg Leu Ser Lys Val Asp Thr Leu Arg Leu Ala Ile Gly Tyr
195 200 205
Ile Asn Phe Leu Ser Glu Leu Val Gln Ala Asp Leu Pro Leu Arg Gly
210 215 220
Ser Gly Ala Gly Gly Cys Gly Gly Pro Gly Gly Ser Arg His Leu Gly
225 230 235 240
Glu Asp Ser Pro Gly Asn Gln Ala Gln Lys Val Ile Ile Cys His Arg
245 250 255
Gly Thr Arg Ser Pro Ser Pro Ser Asp Pro Asp Tyr Gly Leu Pro Pro
260 265 270
Leu Ala Gly His Ser Leu Ser Trp Thr Asp Glu Lys Gln Leu Lys Glu
275 280 285
Gln Asn Ile Ile Arg Thr Ala Lys Val Trp Thr Pro Glu Asp Pro Arg
290 295 300
Lys Leu Asn Ser Lys Ser Phe Asp Asn Ile Glu Asn Glu Pro Pro Phe
305 310 315 320
Glu Phe Val Ser
<210> 31
<211> 987
<212> DNA
<213> 人
<400> 31
atggacgcgg tgttgctgga gcacttcccc gggggcctag acgcctttcc ttcttcgtac 60
ttcgacgagg acgacttctt caccgaccag tcttcacggg accccctgga ggacggcgat 120
gagctgctgg cggacgagca ggccgaggtg gagttcctta gccaccagct ccacgagtac 180
tgctaccgcg acggggcgtg cctgctgctg cagcccgcgc ccccggccgc cccgctagcg 240
ctcgccccgc cgtcctcggg gggcctcggt gagccagacg acggcggcgg cggcggctac 300
tgctgcgaga cgggggcgcc cccaggcggc ttcccctact cgcccggctc gccgccctcg 360
tgcctggcct acccgtgcgc cggggcggca gtactgtctc ccggggcgcg gctgcgcggc 420
ctgagcggag cggcggctgc ggcggcgcgg cgccggcggc gggtgcgctc cgaggcggag 480
ctgcagcagc tgcggcaggc ggccaacgtg cgcgagcggc ggcgcatgca gtccatcaac 540
gacgccttcg aggggctgcg ctcgcacatc cccacgctgc cctacgagaa gcgcctctcc 600
aaggtggaca cgctgcgcct ggccatcggc tacatcaact tcctcagcga gctcgtgcag 660
gccgacctgc ccttgcgcgg cggtggcgcg ggcggctgcg gggggccggg cggcggcggg 720
cgcctgggcg gggacagccc gggcagccag gcccagaagg tcatcatctg ccatcggggc 780
acccggtccc cctcccccag cgaccctgat tatggcctcc ctcccctagc aggacactct 840
ctctcatgga ctgatgaaaa acaactcaag gaacaaaata ttatccgaac agccaaagtc 900
tggaccccag aggaccccag aaaactcaac agcaaatctt ccttcaacaa catagaaaac 960
gaaccaccat ttgagtttgt gtcctga 987
<210> 32
<211> 975
<212> DNA
<213> 小鼠
<400> 32
atggacgccg tactcctgga gcacttcccc gggggcctgg acaccttccc atccccttac 60
tttgatgagg aagatttctt caccgaccag tcctctcggg acccgctgga ggacagcgac 120
gagctgctgg gggacgagca agcagaagta gagttcctca gccaccagct acacgaatac 180
tgctaccgcg acggggcgtg cctgctgctg caacccgcgc cctcggccgc cccgcacgcg 240
ctcgccccgc cgcctttggg ggatcctggc gagcccgagg acaacgtcag ctattgctgc 300
gatgcagggg ctcctctcgc tgccttcccc tactcgcctg gctcaccgcc ctcgtgcctc 360
gcctacccgt gtgccgcggt gctgtccccc ggtgcgcggc tcggtggttt gaacggggct 420
gcggcagcgg cggcagcaag gcggcggcga cgcgtgcgct ccgaggcgga gctgcagcag 480
ctgcgacaag ccgctaatgt gcgagagcgg cgccgcatgc agtccatcaa cgacgccttc 540
gaggggctgc gttcgcacat ccccacgcta ccctacgaaa agcgcctctc caaagtagac 600
acgctgcgct tggccatagg ctacattaac ttcctcagcg agctggtgca agccgacctg 660
ccgctgcgcg ggagtggcgc aggtggttgc gggggcccag gtggcagccg gcacctcgga 720
gaggacagtc ccggtaacca ggcccagaag gttatcatct gccatcgagg cacccgttca 780
ccctccccca gtgacccgga ttatggtctc cctcctcttg cagggcactc tctttcctgg 840
actgatgaaa aacagctcaa agaacaaaat atcatccgta cagctaaagt gtggacccca 900
gaggacccca gaaaactcaa cagtaaatct ttcgacaaca tagagaacga accacccttt 960
gagtttgtgt cctga 975
<210> 33
<211> 422
<212> PRT
<213> 人
<400> 33
Met Gln Asn Ser His Ser Gly Val Asn Gln Leu Gly Gly Val Phe Val
1 5 10 15
Asn Gly Arg Pro Leu Pro Asp Ser Thr Arg Gln Lys Ile Val Glu Leu
20 25 30
Ala His Ser Gly Ala Arg Pro Cys Asp Ile Ser Arg Ile Leu Gln Val
35 40 45
Ser Asn Gly Cys Val Ser Lys Ile Leu Gly Arg Tyr Tyr Glu Thr Gly
50 55 60
Ser Ile Arg Pro Arg Ala Ile Gly Gly Ser Lys Pro Arg Val Ala Thr
65 70 75 80
Pro Glu Val Val Ser Lys Ile Ala Gln Tyr Lys Arg Glu Cys Pro Ser
85 90 95
Ile Phe Ala Trp Glu Ile Arg Asp Arg Leu Leu Ser Glu Gly Val Cys
100 105 110
Thr Asn Asp Asn Ile Pro Ser Val Ser Ser Ile Asn Arg Val Leu Arg
115 120 125
Asn Leu Ala Ser Glu Lys Gln Gln Met Gly Ala Asp Gly Met Tyr Asp
130 135 140
Lys Leu Arg Met Leu Asn Gly Gln Thr Gly Ser Trp Gly Thr Arg Pro
145 150 155 160
Gly Trp Tyr Pro Gly Thr Ser Val Pro Gly Gln Pro Thr Gln Asp Gly
165 170 175
Cys Gln Gln Gln Glu Gly Gly Gly Glu Asn Thr Asn Ser Ile Ser Ser
180 185 190
Asn Gly Glu Asp Ser Asp Glu Ala Gln Met Arg Leu Gln Leu Lys Arg
195 200 205
Lys Leu Gln Arg Asn Arg Thr Ser Phe Thr Gln Glu Gln Ile Glu Ala
210 215 220
Leu Glu Lys Glu Phe Glu Arg Thr His Tyr Pro Asp Val Phe Ala Arg
225 230 235 240
Glu Arg Leu Ala Ala Lys Ile Asp Leu Pro Glu Ala Arg Ile Gln Val
245 250 255
Trp Phe Ser Asn Arg Arg Ala Lys Trp Arg Arg Glu Glu Lys Leu Arg
260 265 270
Asn Gln Arg Arg Gln Ala Ser Asn Thr Pro Ser His Ile Pro Ile Ser
275 280 285
Ser Ser Phe Ser Thr Ser Val Tyr Gln Pro Ile Pro Gln Pro Thr Thr
290 295 300
Pro Val Ser Ser Phe Thr Ser Gly Ser Met Leu Gly Arg Thr Asp Thr
305 310 315 320
Ala Leu Thr Asn Thr Tyr Ser Ala Leu Pro Pro Met Pro Ser Phe Thr
325 330 335
Met Ala Asn Asn Leu Pro Met Gln Pro Pro Val Pro Ser Gln Thr Ser
340 345 350
Ser Tyr Ser Cys Met Leu Pro Thr Ser Pro Ser Val Asn Gly Arg Ser
355 360 365
Tyr Asp Thr Tyr Thr Pro Pro His Met Gln Thr His Met Asn Ser Gln
370 375 380
Pro Met Gly Thr Ser Gly Thr Thr Ser Thr Gly Leu Ile Ser Pro Gly
385 390 395 400
Val Ser Val Pro Val Gln Val Pro Gly Ser Glu Pro Asp Met Ser Gln
405 410 415
Tyr Trp Pro Arg Leu Gln
420
<210> 34
<211> 436
<212> PRT
<213> 小鼠
<400> 34
Met Gln Asn Ser His Ser Gly Val Asn Gln Leu Gly Gly Val Phe Val
1 5 10 15
Asn Gly Arg Pro Leu Pro Asp Ser Thr Arg Gln Lys Ile Val Glu Leu
20 25 30
Ala His Ser Gly Ala Arg Pro Cys Asp Ile Ser Arg Ile Leu Gln Thr
35 40 45
His Ala Asp Ala Lys Val Gln Val Leu Asp Asn Glu Asn Val Ser Asn
50 55 60
Gly Cys Val Ser Lys Ile Leu Gly Arg Tyr Tyr Glu Thr Gly Ser Ile
65 70 75 80
Arg Pro Arg Ala Ile Gly Gly Ser Lys Pro Arg Val Ala Thr Pro Glu
85 90 95
Val Val Ser Lys Ile Ala Gln Tyr Lys Arg Glu Cys Pro Ser Ile Phe
100 105 110
Ala Trp Glu Ile Arg Asp Arg Leu Leu Ser Glu Gly Val Cys Thr Asn
115 120 125
Asp Asn Ile Pro Ser Val Ser Ser Ile Asn Arg Val Leu Arg Asn Leu
130 135 140
Ala Ser Glu Lys Gln Gln Met Gly Ala Asp Gly Met Tyr Asp Lys Leu
145 150 155 160
Arg Met Leu Asn Gly Gln Thr Gly Ser Trp Gly Thr Arg Pro Gly Trp
165 170 175
Tyr Pro Gly Thr Ser Val Pro Gly Gln Pro Thr Gln Asp Gly Cys Gln
180 185 190
Gln Gln Glu Gly Gly Gly Glu Asn Thr Asn Ser Ile Ser Ser Asn Gly
195 200 205
Glu Asp Ser Asp Glu Ala Gln Met Arg Leu Gln Leu Lys Arg Lys Leu
210 215 220
Gln Arg Asn Arg Thr Ser Phe Thr Gln Glu Gln Ile Glu Ala Leu Glu
225 230 235 240
Lys Glu Phe Glu Arg Thr His Tyr Pro Asp Val Phe Ala Arg Glu Arg
245 250 255
Leu Ala Ala Lys Ile Asp Leu Pro Glu Ala Arg Ile Gln Val Trp Phe
260 265 270
Ser Asn Arg Arg Ala Lys Trp Arg Arg Glu Glu Lys Leu Arg Asn Gln
275 280 285
Arg Arg Gln Ala Ser Asn Thr Pro Ser His Ile Pro Ile Ser Ser Ser
290 295 300
Phe Ser Thr Ser Val Tyr Gln Pro Ile Pro Gln Pro Thr Thr Pro Val
305 310 315 320
Ser Ser Phe Thr Ser Gly Ser Met Leu Gly Arg Thr Asp Thr Ala Leu
325 330 335
Thr Asn Thr Tyr Ser Ala Leu Pro Pro Met Pro Ser Phe Thr Met Ala
340 345 350
Asn Asn Leu Pro Met Gln Pro Pro Val Pro Ser Gln Thr Ser Ser Tyr
355 360 365
Ser Cys Met Leu Pro Thr Ser Pro Ser Val Asn Gly Arg Ser Tyr Asp
370 375 380
Thr Tyr Thr Pro Pro His Met Gln Thr His Met Asn Ser Gln Pro Met
385 390 395 400
Gly Thr Ser Gly Thr Thr Ser Thr Gly Leu Ile Ser Pro Gly Val Ser
405 410 415
Val Pro Val Gln Val Pro Gly Ser Glu Pro Asp Met Ser Gln Tyr Trp
420 425 430
Pro Arg Leu Gln
435
<210> 35
<211> 1269
<212> DNA
<213> 人
<400> 35
atgcagaaca gtcacagcgg agtgaatcag ctcggtggtg tctttgtcaa cgggcggcca 60
ctgccggact ccacccggca gaagattgta gagctagctc acagcggggc ccggccgtgc 120
gacatttccc gaattctgca ggtgtccaac ggatgtgtga gtaaaattct gggcaggtat 180
tacgagactg gctccatcag acccagggca atcggtggta gtaaaccgag agtagcgact 240
ccagaagttg taagcaaaat agcccagtat aagcgggagt gcccgtccat ctttgcttgg 300
gaaatccgag acagattact gtccgagggg gtctgtacca acgataacat accaagcgtg 360
tcatcaataa acagagttct tcgcaacctg gctagcgaaa agcaacagat gggcgcagac 420
ggcatgtatg ataaactaag gatgttgaac gggcagaccg gaagctgggg cacccgccct 480
ggttggtatc cggggacttc ggtgccaggg caacctacgc aagatggctg ccagcaacag 540
gaaggagggg gagagaatac caactccatc agttccaacg gagaagattc agatgaggct 600
caaatgcgac ttcagctgaa gcggaagctg caaagaaata gaacatcctt tacccaagag 660
caaattgagg ccctggagaa agagtttgag agaacccatt atccagatgt gtttgcccga 720
gaaagactag cagccaaaat agatctacct gaagcaagaa tacaggtatg gttttctaat 780
cgaagggcca aatggagaag agaagaaaaa ctgaggaatc agagaagaca ggccagcaac 840
acacctagtc atattcctat cagcagtagt ttcagcacca gtgtctacca accaattcca 900
caacccacca caccggtttc ctccttcaca tctggctcca tgttgggccg aacagacaca 960
gccctcacaa acacctacag cgctctgccg cctatgccca gcttcaccat ggcaaataac 1020
ctgcctatgc aacccccagt ccccagccag acctcctcat actcctgcat gctgcccacc 1080
agcccttcgg tgaatgggcg gagttatgat acctacaccc ccccacatat gcagacacac 1140
atgaacagtc agccaatggg cacctcgggc accacttcaa caggactcat ttcccctggt 1200
gtgtcagttc cagttcaagt tcccggaagt gaacctgata tgtctcaata ctggccaaga 1260
ttacagtaa 1269
<210> 36
<211> 1311
<212> DNA
<213> 小鼠
<400> 36
atgcagaaca gtcacagcgg agtgaatcag cttggtggtg tctttgtcaa cgggcggcca 60
ctgccggact ccacccggca gaagatcgta gagctagctc acagcggggc ccggccgtgc 120
gacatttccc gaattctgca gacccatgca gatgcaaaag tccaggtgct ggacaatgaa 180
aacgtatcca acggttgtgt gagtaaaatt ctgggcaggt attacgagac tggctccatc 240
agacccaggg caatcggagg gagtaagcca agagtggcga ctccagaagt tgtaagcaaa 300
atagcccagt ataaacggga gtgcccttcc atctttgctt gggaaatccg agacagatta 360
ttatccgagg gggtctgtac caacgataac atacccagtg tgtcatcaat aaacagagtt 420
cttcgcaacc tggctagcga aaagcaacag atgggcgcag acggcatgta tgataaacta 480
aggatgttga acgggcagac cggaagctgg ggcacacgcc ctggttggta tcccgggact 540
tcagtaccag ggcaacccac gcaagatggc tgccagcaac aggaaggagg gggagagaac 600
accaactcca tcagttctaa cggagaagac tcggatgaag ctcagatgcg acttcagctg 660
aagcggaagc tgcaaagaaa tagaacatct tttacccaag agcagattga ggctctggag 720
aaagagtttg agaggaccca ttatccagat gtgtttgccc gggaaagact agcagccaaa 780
atagatctac ctgaagcaag aatacaggta tggttttcta atcgaagggc caaatggaga 840
agagaagaga aactgaggaa ccagagaaga caggccagca acactcctag tcacattcct 900
atcagcagca gcttcagtac cagtgtctac cagccaatcc cacagcccac cacacctgtc 960
tcctccttca catcaggttc catgttgggc cgaacagaca ccgccctcac caacacgtac 1020
agtgctttgc cacccatgcc cagcttcacc atggcaaaca acctgcctat gcaaccccca 1080
gtccccagtc agacctcctc atactcgtgc atgctgccca ccagcccgtc agtgaatggg 1140
cggagttatg atacctacac ccctccgcac atgcaaacac acatgaacag tcagcccatg 1200
ggcacctcgg ggaccacttc aacaggactc atttcacctg gagtgtcagt tcccgtccaa 1260
gttcccggga gtgaacctga catgtctcag tactggcctc gattacagta a 1311
<210> 37
<211> 289
<212> PRT
<213> 人
<400> 37
Met Met Ser Tyr Leu Lys Gln Pro Pro Tyr Ala Val Asn Gly Leu Ser
1 5 10 15
Leu Thr Thr Ser Gly Met Asp Leu Leu His Pro Ser Val Gly Tyr Pro
20 25 30
Ala Thr Pro Arg Lys Gln Arg Arg Glu Arg Thr Thr Phe Thr Arg Ala
35 40 45
Gln Leu Asp Val Leu Glu Ala Leu Phe Ala Lys Thr Arg Tyr Pro Asp
50 55 60
Ile Phe Met Arg Glu Glu Val Ala Leu Lys Ile Asn Leu Pro Glu Ser
65 70 75 80
Arg Val Gln Val Trp Phe Lys Asn Arg Arg Ala Lys Cys Arg Gln Gln
85 90 95
Gln Gln Gln Gln Gln Asn Gly Gly Gln Asn Lys Val Arg Pro Ala Lys
100 105 110
Lys Lys Thr Ser Pro Ala Arg Glu Val Ser Ser Glu Ser Gly Thr Ser
115 120 125
Gly Gln Phe Thr Pro Pro Ser Ser Thr Ser Val Pro Thr Ile Ala Ser
130 135 140
Ser Ser Ala Pro Val Ser Ile Trp Ser Pro Ala Ser Ile Ser Pro Leu
145 150 155 160
Ser Asp Pro Leu Ser Thr Ser Ser Ser Cys Met Gln Arg Ser Tyr Pro
165 170 175
Met Thr Tyr Thr Gln Ala Ser Gly Tyr Ser Gln Gly Tyr Ala Gly Ser
180 185 190
Thr Ser Tyr Phe Gly Gly Met Asp Cys Gly Ser Tyr Leu Thr Pro Met
195 200 205
His His Gln Leu Pro Gly Pro Gly Ala Thr Leu Ser Pro Met Gly Thr
210 215 220
Asn Ala Val Thr Ser His Leu Asn Gln Ser Pro Ala Ser Leu Ser Thr
225 230 235 240
Gln Gly Tyr Gly Ala Ser Ser Leu Gly Phe Asn Ser Thr Thr Asp Cys
245 250 255
Leu Asp Tyr Lys Asp Gln Thr Ala Ser Trp Lys Leu Asn Phe Asn Ala
260 265 270
Asp Cys Leu Asp Tyr Lys Asp Gln Thr Ser Ser Trp Lys Phe Gln Val
275 280 285
Leu
<210> 38
<211> 297
<212> PRT
<213> 小鼠
<400> 38
Met Met Ser Tyr Leu Lys Gln Pro Pro Tyr Ala Val Asn Gly Leu Ser
1 5 10 15
Leu Thr Thr Ser Gly Met Asp Leu Leu His Pro Ser Val Gly Tyr Pro
20 25 30
Gly Pro Trp Ala Ser Cys Pro Ala Ala Thr Pro Arg Lys Gln Arg Arg
35 40 45
Glu Arg Thr Thr Phe Thr Arg Ala Gln Leu Asp Val Leu Glu Ala Leu
50 55 60
Phe Ala Lys Thr Arg Tyr Pro Asp Ile Phe Met Arg Glu Glu Val Ala
65 70 75 80
Leu Lys Ile Asn Leu Pro Glu Ser Arg Val Gln Val Trp Phe Lys Asn
85 90 95
Arg Arg Ala Lys Cys Arg Gln Gln Gln Gln Gln Gln Gln Asn Gly Gly
100 105 110
Gln Asn Lys Val Arg Pro Ala Lys Lys Lys Ser Ser Pro Ala Arg Glu
115 120 125
Val Ser Ser Glu Ser Gly Thr Ser Gly Gln Phe Ser Pro Pro Ser Ser
130 135 140
Thr Ser Val Pro Thr Ile Ala Ser Ser Ser Ala Pro Val Ser Ile Trp
145 150 155 160
Ser Pro Ala Ser Ile Ser Pro Leu Ser Asp Pro Leu Ser Thr Ser Ser
165 170 175
Ser Cys Met Gln Arg Ser Tyr Pro Met Thr Tyr Thr Gln Ala Ser Gly
180 185 190
Tyr Ser Gln Gly Tyr Ala Gly Ser Thr Ser Tyr Phe Gly Gly Met Asp
195 200 205
Cys Gly Ser Tyr Leu Thr Pro Met His His Gln Leu Pro Gly Pro Gly
210 215 220
Ala Thr Leu Ser Pro Met Gly Thr Asn Ala Val Thr Ser His Leu Asn
225 230 235 240
Gln Ser Pro Ala Ser Leu Ser Thr Gln Gly Tyr Gly Ala Ser Ser Leu
245 250 255
Gly Phe Asn Ser Thr Thr Asp Cys Leu Asp Tyr Lys Asp Gln Thr Ala
260 265 270
Ser Trp Lys Leu Asn Phe Asn Ala Asp Cys Leu Asp Tyr Lys Asp Gln
275 280 285
Thr Ser Ser Trp Lys Phe Gln Val Leu
290 295
<210> 39
<211> 870
<212> DNA
<213> 人
<400> 39
atgatgtctt atcttaagca accgccttac gcagtcaatg ggctgagtct gaccacttcg 60
ggtatggact tgctgcaccc ctccgtgggc tacccggcca ccccccggaa acagcgccgg 120
gagaggacga cgttcactcg ggcgcagcta gatgtgctgg aagcactgtt tgccaagacc 180
cggtacccag acatcttcat gcgagaggag gtggcactga aaatcaactt gcccgagtcg 240
agggtgcagg tatggtttaa gaatcgaaga gctaagtgcc gccaacaaca gcaacaacag 300
cagaatggag gtcaaaacaa agtgagacct gccaaaaaga agacatctcc agctcgggaa 360
gtgagttcag agagtggaac aagtggccaa ttcactcccc cctctagcac ctcagtcccg 420
accattgcca gcagcagtgc tcctgtgtct atctggagcc cagcttccat ctccccactg 480
tcagatccct tgtccacctc ctcttcctgc atgcagaggt cctatcccat gacctatact 540
caggcttcag gttatagtca aggatatgct ggctcaactt cctactttgg gggcatggac 600
tgtggatcat atttgacccc tatgcatcac cagcttcccg gaccaggggc cacactcagt 660
cccatgggta ccaatgcagt caccagccat ctcaatcagt ccccagcttc tctttccacc 720
cagggatatg gagcttcaag cttgggtttt aactcaacca ctgattgctt ggattataag 780
gaccaaactg cctcctggaa gcttaacttc aatgctgact gcttggatta taaagatcag 840
acatcctcgt ggaaattcca ggttttgtga 870
<210> 40
<211> 894
<212> DNA
<213> 小鼠
<400> 40
atgatgtctt atctaaagca accgccttac gcagtcaatg ggctgagtct gaccacttcg 60
ggtatggact tgctgcatcc ctccgtgggc taccccgggc cctgggcttc ttgtcctgca 120
gccacccccc ggaaacagcg aagggagagg acgacattta ctagggcaca gctcgacgtt 180
ctggaagctc tgtttgccaa gacccggtac ccagacatct tcatgaggga agaggtggca 240
ctgaaaatca acttgccaga atccagggtg caggtatggt ttaagaatcg aagagctaag 300
tgccgccaac agcagcagca gcagcagaat ggaggtcaga acaaagtgag gcctgccaag 360
aagaagagct ctccagctcg ggaagtgagt tcagagagtg gaacaagtgg ccagttcagt 420
cccccctcta gtacctcagt cccaaccatt gccagcagca gtgctccagt gtctatctgg 480
agcccagcgt ccatctcccc actgtctgac cccttgtcca cttcctcctc ctgcatgcag 540
aggtcctatc ccatgaccta tactcaggct tcaggttata gtcaaggcta tgctggctca 600
acttcctact ttgggggcat ggactgtgga tcttatttga cccctatgca tcaccagctt 660
cctggaccag gggccacact cagtcccatg ggtaccaatg ctgttaccag ccatctcaat 720
cagtccccag cttctctttc cacccaggga tatggagctt caagcttggg ttttaactca 780
accactgatt gcttggatta taaggaccaa actgcctctt ggaagcttaa cttcaatgct 840
gactgcttgg attataaaga tcagacgtcc tcatggaaat tccaggtttt gtga 894
<210> 41
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 人工改造
<400> 41
Met Glu Ser Ser Ala Lys Met Glu Ser Gly Gly Ala Gly Gln Gln Pro
1 5 10 15
Gln Pro Gln Pro Gln Gln Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe
20 25 30
Ala Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Gln
35 40 45
Ser Ala Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ala Pro
50 55 60
Gln Leu Arg Pro Ala Ala Asp Gly Gln Pro Ser Gly Gly Gly His Lys
65 70 75 80
Ser Ala Pro Lys Gln Val Lys Arg Gln Arg Ser Ser Ala Pro Glu Leu
85 90 95
Met Arg Cys Lys Arg Arg Leu Asn Phe Ser Gly Phe Gly Tyr Ser Leu
100 105 110
Pro Gln Gln Gln Pro Ala Ala Val Ala Arg Arg Asn Glu Arg Glu Arg
115 120 125
Asn Arg Val Lys Leu Val Asn Leu Gly Phe Ala Thr Leu Arg Glu His
130 135 140
Val Pro Asn Gly Ala Ala Asn Lys Lys Met Ser Lys Val Glu Thr Leu
145 150 155 160
Arg Ser Ala Val Glu Tyr Ile Arg Ala Leu Gln Gln Leu Leu Asp Glu
165 170 175
His Asp Ala Val Ser Ala Ala Phe Gln Ala Gly Val Leu Ala Pro Thr
180 185 190
Ile Ala Pro Asn Tyr Ser Asn Asp Leu Asn Ser Met Ala Gly Ala Pro
195 200 205
Val Ser Ser Tyr Ser Ser Asp Glu Gly Ser Tyr Asp Pro Leu Ala Pro
210 215 220
Glu Glu Gln Glu Leu Leu Asp Phe Thr Asn Trp Phe
225 230 235
<210> 42
<211> 2209
<212> DNA
<213> 人
<400> 42
taatcccacc tccctctctg tgctgggact cacagaggga gacctcagga ggcagtctgt 60
ccatcacatg tccaaatgca gagcataccc tgggctgggc gcagtggcgc acaactgtaa 120
ttccagcact ttgggaggct gatgtggaag gatcacttga gcccagaagt tctagaccag 180
cctgggcaac atggcaagac cctatctcta caaaaaaagt taaaaaatca gccacgtgtg 240
gtgacacaca cctgtagtcc cagctattca ggaggctgag gtgaggggat cacttaaggc 300
tgggaggttg aggctgcagt gagtcgtggt tgcgccactg cactccagcc tgggcaacag 360
tgagaccctg tctcaaaaga caaaaaaaaa aaaaaaaaaa aaagaacata tcctggtgtg 420
gagtagggga cgctgctctg acagaggctc gggggcctga gctggctctg tgagctgggg 480
aggaggcaga cagccaggcc ttgtctgcaa gcagacctgg cagcattggg ctggccgccc 540
cccagggcct cctcttcatg cccagtgaat gactcacctt ggcacagaca caatgttcgg 600
ggtgggcaca gtgcctgctt cccgccgcac cccagccccc ctcaaatgcc ttccgagaag 660
cccattgagc agggggcttg cattgcaccc cagcctgaca gcctggcatc ttgggataaa 720
agcagcacag ccccctaggg gctgcccttg ctgtgtggcg ccaccggcgg tggagaacaa 780
ggctctattc agcctgtgcc caggaaaggg gatcagggga tgcccaggca tggacagtgg 840
gtggcagggg gggagaggag ggctgtctgc ttcccagaag tccaaggaca caaatgggtg 900
aggggactgg gcagggttct gaccctgtgg gaccagagtg gagggcgtag atggacctga 960
agtctccagg gacaacaggg cccaggtctc aggctcctag ttgggcccag tggctccagc 1020
gtttccaaac ccatccatcc ccagaggttc ttcccatctc tccaggctga tgtgtgggaa 1080
ctcgaggaaa taaatctcca gtgggagacg gaggggtggc cagggaaacg gggcgctgca 1140
ggaataaaga cgagccagca cagccagctc atgtgtaacg gctttgtgga gctgtcaagg 1200
cctggtctct gggagagagg cacagggagg ccagacaagg aaggggtgac ctggagggac 1260
agatccaggg gctaaagtcc tgataaggca agagagtgcc ggccccctct tgccctatca 1320
ggacctccac tgccacatag aggccatgat tgacccttag acaaagggct ggtgtccaat 1380
cccagccccc agccccagaa ctccagggaa tgaatgggca gagagcagga atgtgggaca 1440
tctgtgttca agggaaggac tccaggagtc tgctgggaat gaggcctagt aggaaatgag 1500
gtggcccttg agggtacaga acaggttcat tcttcgccaa attcccagca ccttgcaggc 1560
acttacagct gagtgagata atgcctgggt tatgaaatca aaaagttgga aagcaggtca 1620
gaggtcatct ggtacagccc ttccttccct tttttttttt tttttttgtg agacaaggtc 1680
tctctctgtt gcccaggctg gagtggcgca aacacagctc actgcagcct caacctactg 1740
ggctcaagca atcctccagc ctcagcctcc caaagtgctg ggattacaag catgagccac 1800
cccactcagc cctttccttc ctttttaatt gatgcataat aattgtaagt attcatcatg 1860
gtccaaccaa ccctttcttg acccaccttc ctagagagag ggtcctcttg cttcagcggt 1920
cagggcccca gacccatggt ctggctccag gtaccacctg cctcatgcag gagttggcgt 1980
gcccaggaag ctctgcctct gggcacagtg acctcagtgg ggtgagggga gctctcccca 2040
tagctgggct gcggcccaac cccaccccct caggctatgc cagggggtgt tgccaggggc 2100
acccgggcat cgccagtcta gcccactcct tcataaagcc ctcgcatccc aggagcgagc 2160
agagccagag caggttggag aggagacgca tcacctccgc tgctcgcgg 2209
<210> 43
<211> 683
<212> DNA
<213> 人工序列
<220>
<223> 人工改造
<400> 43
aacatatcct ggtgtggagt aggggacgct gctctgacag aggctcgggg gcctgagctg 60
gctctgtgag ctggggagga ggcagacagc caggccttgt ctgcaagcag acctggcagc 120
attgggctgg ccgcccccca gggcctcctc ttcatgccca gtgaatgact caccttggca 180
cagacacaat gttcggggtg ggcacagtgc ctgcttcccg ccgcacccca gcccccctca 240
aatgccttcc gagaagccca ttgagcaggg ggcttgcatt gcaccccagc ctgacagcct 300
ggcatcttgg gataaaagca gcacagcccc ctaggggctg cccttgctgt gtggcgccac 360
cggcggtgga gaacaaggct ctattcagcc tgtgcccagg aaaggggatc aggggatgcc 420
caggcatgga cagtgggtgg caggggggga gaggagggct gtctgcttcc cagaagtcca 480
aggacacaaa tgggtgaggg gagagctctc cccatagctg ggctgcggcc caaccccacc 540
ccctcaggct atgccagggg gtgttgccag gggcacccgg gcatcgccag tctagcccac 600
tccttcataa agccctcgca tcccaggagc gagcagagcc agagcaggtt ggagaggaga 660
cgcatcacct ccgctgctcg cgg 683
<210> 44
<211> 45
<212> PRT
<213> 单纯疱疹病毒
<400> 44
Met Leu Gly Asp Gly Asp Ser Pro Gly Pro Gly Phe Thr Pro His Asp
1 5 10 15
Ser Ala Pro Tyr Gly Ala Leu Asp Met Ala Asp Phe Glu Phe Glu Gln
20 25 30
Met Phe Thr Asp Ala Leu Gly Ile Asp Glu Tyr Gly Gly
35 40 45
<210> 45
<211> 135
<212> DNA
<213> 单纯疱疹病毒
<400> 45
atgttggggg acggggattc cccgggtccg ggatttaccc cccacgactc cgccccctac 60
ggcgctctgg atatggccga cttcgagttt gagcagatgt ttaccgatgc ccttggaatt 120
gacgagtacg gtggg 135
<210> 46
<211> 237
<212> DNA
<213> 猴空泡病毒40
<400> 46
cgatggagcg gagaatgggc ggaactgggc ggagttaggg gcgggatggg cggagttagg 60
ggcgggacta tggttgctga ctaattgaga tgcatgcttt gcatacttct gcctgctggg 120
gagcctgggg actttccaca cctggttgct gactaattga gatgcatgct ttgcatactt 180
ctgcctgctg gggagcctgg ggactttcca caccctaact gacacacatt ccacagc 237
Claims (10)
1.一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的功能性片段含有至少一个促进转录因子表达的功能性片段,所述的功能性片段选自能促进NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2转录因子表达的功能性片段。
2.如权利要求1所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的功能性片段含有至少二个促进转录因子表达的功能性片段,所述的功能性片段选自能促进NeuroD1、Brn2、Ascl1、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6和/或Otx2转录因子表达的功能性片段;优选地,所述的功能性片段至少含有促进Ascl1或Ngn2任一的转录因子表达的功能性片段。
3.如权利要求1所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的功能性片段至少含有促进NeuroD1与Brn2两个转录因子表达的功能性片段、或促进Gsx1与Tbr1两个转录因子表达的功能性片段、或促进Dlx2与Ptf1a两个转录因子表达的功能性片段、或促进Pax6与Otx2两个转录因子表达的功能性片段;优选地,所述的功能性片段还含有促进Ascl1或Ngn2转录因子表达的功能性片段。
4.如权利要求1所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的功能性片段选自编码所述转录因子的多核苷酸,或多核苷酸转译后的功能性的蛋白、多肽,或促进转录因子表达小分子药物、大分子药物、核酸药物,或位于所述转录因子上游调控转录因子表达上调的多核苷酸或功能性蛋白、多肽、小分子药物或大分子药物、核酸药物。
5.如权利要求4所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的功能性片段选自与SEQ ID NO.:1、2、5、6、9、10、13、14、17、18、21、22、25、26、29、30、33、34、37、38和/或41的序列同源性不低于85%的转录因子功能性蛋白或选自与SEQ ID NO.:3、4、7、8、11、12、15、16、19、20、23、24、27、28、31、32、35、36、39和/或40的序列同源性不低于75%的编码转录因子的多核苷酸;优选地,所述的功能性片段选自与SEQ ID NO.:1、2、5、6、9、10、13、14、17、18、21、22、25、26、29、30、33、34、37、38和/或41的序列同源性不低于95%的转录因子功能性蛋白或选自与SEQ ID NO.:3、4、7、8、11、12、15、16、19、20、23、24、27、28、31、32、35、36、39和/或40的序列同源性不低于85%的编码转录因子的多核苷酸;最优地,所述的功能性片段选自与SEQ ID NO.:1、2、5、6、9、10、13、14、17、18、21、22、25、26、29、30、33、34、37、38和/或41的序列同源性不低于99%的转录因子功能性蛋白或选自与SEQ ID NO.:3、4、7、8、11、12、15、16、19、20、23、24、27、28、31、32、35、36、39和/或40的序列同源性不低于95%的编码转录因子的多核苷酸。
6.如权利要求1所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述促进转录因子表达的功能性片段可通过与所述胶质细胞直接接触、或递送系统导入的方式,促进胶质细胞中相关转录因子的表达增高,并展现出功能性神经细胞或类神经细胞的特征;
所述的胶质细胞选自星形胶质细胞、NG2胶质细胞、少突胶质细胞、小胶质细胞、或处于损伤状态下的胶质细胞、胶质细胞来源的肿瘤细胞;
所述的递送系统选自载有促进转录因子表达的功能性片段的表达载体、包裹有促进转录因子表达的功能性片段的纳米颗粒、包裹促进转录因子表达的功能性片段的外泌体、包裹有促进转录因子表达的功能性片段的病毒载体或细胞载体、挂载有促进转录因子表达的功能性片段的靶向效应物;
所述的递送系统中还载有胶质细胞特异性的启动子、或者表达调控元件。
7.如权利要求6所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的促进转录因子表达的功能性片段的表达体系可以构建在同一个表达载体之下,或使用不同的表达载体分别表达,其中:
(1)当存在任2个促进转录因子表达的功能性片段时,两个转录因子的表达量的摩尔浓度比为4:1~1:4;优选地两种转录因子的表达量的摩尔浓度比为2:1~1:2;最优地,两种转录因子的表达量的最优摩尔浓度比例为1:1;或
(2)当存在2个及以上促进转录因子表达的功能性片段时,其中一个促进转录因子表达的功能性片段为促进Ascl1或Ngn2转录因子表达的功能性片段时,Ascl1或Ngn2的表达量的摩尔浓度比例不应低于20%,优选地,Ascl1或Ngn2的表达量的摩尔浓度比例不应低于33%;最优地,Ascl1或Ngn2的表达量的摩尔浓度比例不应低于50%。
8.如权利要求7所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的促进转录因子表达的功能性片段选自:
(1)促进NeuroD1与Brn2的转录因子表达的功能性片段的组合;
(2)促进Gsx1与Tbr1的转录因子表达的功能性片段的组合;
(3)促进Dlx2与Ptf1a的转录因子表达的功能性片段的组合;
(4)促进Pax6与Otx2的转录因子表达的功能性片段组合;
(5)促进Ascl1与其他任一转录因子表达的功能性片段组合,另一转录因子选自NeuroD1、Brn2、Ngn2、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2;
(6)促进Ngn2与其他任一转录因子表达的功能性片段组合,另一转录因子选自NeuroD1、Brn2、Ascl1、Gsx1、Tbr1、Dlx2、Ptf1a、Pax6或Otx2。
9.如权利要求7所述的一组可协同促进胶质细胞转分化的功能性片段,其特征在于,所述的促进转录因子表达的功能性片段选自:
(1)促进Ascl1、NeuroD1与Brn2的转录因子表达的功能性片段的组合;
(2)促进Ascl1、Gsx1与Tbr1的转录因子表达的功能性片段的组合;
(3)促进Ascl1、Dlx2与Ptf1a的转录因子表达的功能性片段的组合;
(4)促进Ascl1、Pax6与Otx2的转录因子表达的功能性片段组合;
(5)促进Ngn2、NeuroD1与Brn2的转录因子表达的功能性片段的组合;
(6)促进Ngn2、Gsx1与Tbr1的转录因子表达的功能性片段的组合;
(7)促进Ngn2、Dlx2与Ptf1a的转录因子表达的功能性片段的组合;
(8)促进Ngn2、Pax6与Otx2的转录因子表达的功能性片段组合;
其中,除Ascl1或Ngn2以外的另外两个转录因子的表达量的摩尔浓度比为4:1~1:4;优选地两种转录因子的表达量的摩尔浓度比为2:1~1:2;最优地,两种转录因子的表达量的最优摩尔浓度比例为1:1。
10.如权利要求1-9任一所述的可协同促进胶质细胞转分化的功能性片段在制备神经系统疾病药物中的应用,其特征在于,所述的神经系统疾病为神经系统疾病,损伤或胶质细胞来源的胶质瘤。
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EP21866017.3A EP4212624A1 (en) | 2020-09-08 | 2021-09-08 | Functional fragment for reprogramming, composition, and application thereof |
KR1020237011913A KR20230082024A (ko) | 2020-09-08 | 2021-09-08 | 재프로그래밍을 위한 기능적 단편, 구성 및 이의 응용 |
US18/024,504 US20240026379A1 (en) | 2020-09-08 | 2021-09-08 | Functional fragment for reprogramming, composition, and application thereof |
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PCT/CN2021/117302 WO2022052964A1 (zh) | 2020-09-08 | 2021-09-08 | 用于重编程的功能性片段、组合及其应用 |
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