Immortalized Human Strital Precursors as a Cell Model of HD

描述（由申请人提供）：亨廷顿氏病的细胞模型对于理解该疾病的细胞生物学和测试潜在的治疗方法非常重要。人诱导多能干细胞（iPSC）模型的最近发展极大地增强了我们在人细胞中建模疾病的能力。作为NINDS资助的HD iPSC联盟的一部分，我们开发了HD的细胞模型。然而，尽管这种模型很有价值，但分化成中等多刺神经元的过程非常漫长、繁琐和昂贵，使得细胞的研究和治疗药物的筛选非常困难。因此，我们现在建议从HD iPS细胞产生永生化的纹状体前体。在特定目标1中，我们将使用分化为纹状体前体的HD和对照iPS细胞，用病毒载体进行永生化，并且 优化用于分化为具有成熟纹状体中等多刺神经元表型的神经元的方案。在具体目标2中，我们将评估细胞的CAG重复扩增依赖性毒性和拯救，并将模型形成为可筛选测定。这些研究结合在一起将允许开发一种新的HD细胞模型，其将具有与iPS细胞模型相似的特征，但更可重复和更易处理。这些细胞应该是非常有价值的研究HD发病机制和筛选新的神经保护疗法。

DESCRIPTION (provided by applicant): Cell models of Huntington's disease have been very important for understanding the cell biology of the disorder and for testing potential therapeutics The recent development of human induced pluripotent stem cell (iPSC) models has greatly enhanced our ability to model disease in human cells. As part of the NINDS funded HD iPSC Consortium, we have developed a cell model of HD. However, as valuable as this model is, the differentiation to medium spiny neurons is very long, cumbersome and expensive, making study of the cells and screening for therapeutics very difficult. We therefore now propose to generate immortalized striatal precursors from the HD iPS cells. In Specific Aim 1, we will use HD and control iPS cells differentiated to striatal precursors for immortalization with viral vectors, and optimize protocols for differentiation to neurons with a mature striatal medium spiny neuron phenotype. In Specific Aim 2, we will assess the cells for CAG- repeat-expansion-dependent toxicity and rescue, and format the model as a screenable assay. These studies taken together will permit the development of a novel cell model of HD which will have features similar to the iPS cell model, but be more reproducible and tractable. These cells should be very valuable for studying HD pathogenesis and for screening for novel neuroprotective therapeutics.