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剂非常重要。人类诱导的多能干细胞（IPSC）模型的最新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财团的一部分，我们开发了HD的细胞模型。然而，尽管该模型很有价值，但与中刺神经元的区分非常长，笨拙且昂贵，因此研究细胞并筛查治疗剂非常困难。因此，我们现在建议从HD IPS细胞产生永生的纹状体前体。在特定的目标1中，我们将使用HD和控制IPS细胞区分为纹状体前体，以使病毒载体永生化，并且 优化具有成熟纹状体培养基神经元表型神经元分化的方案。在特定的目标2中，我们将评估细胞的CAG-重复膨胀依赖性毒性和救援，并将模型格式化为可筛选的测定。这些研究一起将允许开发一个新型HD细胞模型，该模型的特征将与IPS细胞模型相似，但更可重现和拖延。这些细胞对于研究HD发病机理和筛查新型神经保护疗法应该非常有价值。