Immortalized Human Strital Precursors as a Cell Model of HD

永生化人类骨骼前体作为 HD 细胞模型

• 批准号: 8533521
• 负责人: Christopher A Ross
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8533521
• 关键词: Agonist; Biochemical; Biological Assay; Brain-Derived Neurotrophic Factor; CAG repeat; Cell Differentiation process; Cell Line; Cell Lineage; Cell model; Cells; Cellular biology; Corpus striatum structure; Development; Disease; Disease model; Funding; Goals; Heterogeneity; Human; Human Development; Huntington Disease; Individual; Knock-in Mouse; Length; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Noise; Pathogenesis; Phenotype; Protocols documentation; Publishing; Rest; Series; Severities; Signal Transduction; Stem cells; Testing; Therapeutic; Toxic effect; Transfection; Viral Vector; human Huntingtin protein; induced pluripotent stem cell; mouse model; mutant; novel; overexpression; public health relevance; relating to nervous system; screening; small molecule

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.

描述（由申请人提供）：亨廷顿病的细胞模型对于了解该疾病的细胞生物学和测试潜在的治疗方法非常重要最近开发的人类诱导多能干细胞（iPSC）模型极大地增强了我们在人类细胞中模拟疾病的能力。作为 NINDS 资助的 HD iPSC 联盟的一部分，我们开发了 HD 细胞模型。然而，尽管该模型很有价值，但分化为中型多棘神经元的时间非常长、繁琐且昂贵，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 细胞中产生永生化纹状体前体。在具体目标 1 中，我们将使用 HD 和对照分化为纹状体前体的 iPS 细胞，通过病毒载体进行永生化，并且 优化分化为具有成熟纹状体中型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，并将模型格式化为可筛选测定。这些研究综合起来将有助于开发一种新型 HD 细胞模型，该模型具有与 iPS 细胞模型相似的特征，但更具可重复性和易处理性。这些细胞对于研究 HD 发病机制和筛选新型神经保护疗法非常有价值。