应用亨廷顿病家系iPS研究引起纹状体GABA能神经元退行性病变的作用机制

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder cuased by an abnormal expansion of CAG repeats. It is presently unknown how the expanded CAG repeats cause degeneration, preferentially in striatal medium spiny GABA neurons. It has no effective treatment. The present proposal, building upon our successful establishment of iPSC lines from a cohort of HD families and our ability to differentiate human iPSCs to enriched populations of functional medium spiny GABA projection neurons, will attempt to uncover the cellular and molecular mechanisms underlying GABA neuron degeneration in HD. (1) to reveal the pathological phenotypes of HD in GABA and other neuronal types that are derived from HD iPSCs in vitro and in vivo; (2) To identify key steps that lead to degeneration of GABA neurons; (3) To correct the pathological phenotypes through genetic correction of the HD mutation by TALENs. The proposed study will most likely build a human disease model for further mechanistic exploration and for drug discovery. It may also reveal potential mechanisms of preferential GABA neuronal degeneration caused by CAG reapeats. Finally, our transgenic correction of HD mutation and transplantation study will set up the foundation for potential future gene/cell therapy with autologous cells.

亨廷顿病（HD）是常染色体显性遗传的神经退行性疾病，由亨廷顿基因中CAG重复序列过度扩增所导致。为什么CAG重复序列扩增会引起神经退行性变，尤其是引起纹状体中等多棘的GABA能投射状神经元特异性病变?目前仍不清楚且没有有效的治疗方法。因此，明确亨廷顿病发病过程中的细胞与分子机制，寻找合理的干预措施，是亟待解决的科学问题。本课题在已建立亨廷顿病家系诱导性干细胞（iPS）基础上，拟进行：1.定向神经分化，揭示亨廷顿病中纹状体GABA能神经元或其它类型神经元的病理表型。并在体外和在体检测病变神经元的功能；2.寻找引起纹状体GABA神经元退行性变过程中关键的调控分子3.应用TALENs技术，修复亨廷顿病iPS中的病变基因，探索修复前后神经元功能的改变。通过本课题的研究，希望建立人的疾病模型，为进一步探索疾病的发病机制和药物筛选提供工具，并为疾病的基因治疗和细胞移植治疗提供实验基础和新思路。

亨廷顿病（HD）是常染色体显性遗传的神经退行性疾病，由亨廷顿基因中CAG重复序列过度扩增所导致。为什么CAG重复序列扩增会引起神经退行性变，尤其是引起纹状体中等多棘的GABA能投射状神经元特异性病变?目前仍不清楚且没有有效的治疗方法。因此，明确亨廷顿病发病过程中的细胞与分子机制，寻找合理的干预措施，是亟待解决的科学问题。本课题建立了亨廷顿病家系诱导性干细胞（iPS）,进行了：1.定向神经分化，揭示亨廷顿病中纹状体GABA能神经元或其它类型神经元的病理表型。并在体外检测了病变神经元和正常神经元表型和功能的异同；2.探索了应用TALENs技术，修复亨廷顿病iPS中的病变基因。虽然探索没有成功,但是也未后续的实验奠定了一定的基础.3.通过本课题的研究，建立了亨廷顿病的细胞模型，为进一步探索疾病的发病机制和药物筛选提供工具。