Generation of trisomy 21 induced pluripotent stem cells

描述（由申请人提供）：唐氏综合症（DS），或21三体，是最常见的导致智力迟钝的遗传性发育障碍。小鼠模型表明神经发生减少和突触发育缺陷是退行性椎体滑移的精神损伤特征的重要因素。虽然小鼠模型至关重要，但它们不能解释人类大脑发育的所有复杂性，因此在人类细胞的背景下检查21三体的影响很重要。对退行性椎体滑移患者的神经发育还没有很好的研究。研究特定细胞类型发育的一种创新方法是利用人类多能干细胞。本探索性提案旨在利用最近报道的诱导多能干细胞（iPS细胞）来创建唐氏综合征特异性多能干细胞，以促进对人类神经发育的分析。该提议的第一个目标是从携带21三体的人类成纤维细胞中诱导多能干细胞。第二个目标是通过测试将这些21三体iPS细胞分化为功能性前脑神经元的可行性来利用这一新资源。这种人类21三体神经元培养模式的建立将使研究能够解剖唐氏综合征中至少三个重要研究重点的分子机制：神经发生，突触发育和功能，以及神经变性。公共卫生相关性：作为最常见的智力迟钝的遗传原因，唐氏综合症是一个公共卫生问题。本研究将建立唐氏综合征的新模型，推动唐氏综合征神经病理生理学的研究。这项提议的目的包括从非胚胎来源制造唐氏综合征特异性人类多能干细胞。

DESCRIPTION (provided by applicant): Down Syndrome (DS), or trisomy 21, is the most common genetic developmental disorder that leads to mental retardation. Mouse models have implicated reduced neurogenesis and faulty synaptic development as important contributors to the mental impairment characteristic of DS. While mouse models are crucial, they cannot explain all the complexities of human brain development making it important to examine the effects of trisomy 21 in the context of human cells. Human neural development in DS has not been well studied. An innovative way to study the development of particular cell types is through the use of human pluripotent stem cells. This exploratory proposal aims to take advantage of recent reports of induced pluripotent stem cells (iPS cells) to create Down syndrome-specific pluripotent stem cells to facilitate analysis of human neural development. The first aim of this proposal is to induce pluripotent stem cells from human fibroblasts that carry the trisomy 21. The second aim will exploit this new resource by testing the feasibility of differentiating these trisomy 21 iPS cells into functional forebrain neurons. The establishment of this human trisomy 21 neuronal culture paradigm will enable studies dissecting the molecular mechanisms of at least three important research priorities in Down syndrome: neurogenesis, synapse development and function, and neurodegeneration. PUBLIC HEALTH RELEVANCE: As the most common genetic cause of mental retardation, Down syndrome is a public health concern. The proposed research will create a new model of Down syndrome to advance the study of Down syndrome neuropathophysiology. The aims of this proposal include making Down syndrome-specific human pluripotent stem cells from non-embryonic sources.