Immortalized Human Strital Precursors as a Cell Model of HD

描述(申请人提供)：亨廷顿病的细胞模型对于了解疾病的细胞生物学和测试潜在的治疗方法非常重要。最近人类诱导多能干细胞(IPSC)模型的发展极大地增强了我们在人类细胞中建模疾病的能力。作为NINDS资助的HD iPSC联盟的一部分，我们开发了一个HD细胞模型。然而，尽管这个模型很有价值，但分化成中等刺状神经元的过程非常漫长、繁琐和昂贵，使得细胞研究和治疗筛选非常困难。因此，我们现在建议从HD iPS细胞中产生永生化的纹状体前体细胞。在特定的目标1中，我们将使用HD和对照iPS细胞分化为纹状体前体细胞，通过病毒载体永生化，以及 优化分化为成熟纹状体中多刺神经元表型的神经元的方案。在特定的目标2中，我们将评估细胞的CAG重复扩增依赖的毒性和拯救，并形成一个可筛选的模型。这些研究将使开发一种新的HD细胞模型成为可能，该模型将具有与iPS细胞模型相似的特征，但更具重复性和易操作性。这些细胞对研究HD的发病机制和筛选新的神经保护治疗药物具有重要价值。

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.