A National iPS Cell Network with Deep Phenotyping for Translational Research

项目概要/摘要 iPSC的发现为任何科学家提供了一个前所未有的机会， 来源于患者的原代细胞的取之不尽的供应。这些细胞含有每个病人自己的基因 背景技术现在可以应用于体外人类疾病建模、个性化药物筛选 治疗，以及未来基于再生细胞的治疗的发展。最有价值的人类 CTSA调查人员就该提案合作生成的克隆不仅携带共同的 疾病相关的突变和多态性，而且还携带敲入荧光染料报告基因 通过最先进的基因编辑技术靶向特定的基因座。这项提案的目的是 建立CTSA诱导多能干细胞（iPSC）库网络， iPSC核心将使用超过1000个现有的正常和疾病模型， 特定的人类细胞系和银行6,000额外的样本采购从第二和第三届 这是一项研究的参与者。 在所有CTSA中协调一致地管理、共享和分发这一重要资源， 存在.因此，该提案创建了一个CTSA iPSC网络，由支持“开放” Source Biology的方法，免费分享iPSC细胞系及其重编程试剂， 到目前为止在地球仪上有500个实验室。它的目标是使患者来源的iPSC与工具一起 和专业知识，为他们的基因操纵提供了更大的研究社区在大规模 以实现他们扩大对疾病的了解和开发潜在疗法的承诺。到 为了实现这些目标，它建议：a）国家共享CTSA已经获得的>1000个iPSC系 在本提案中合作的团队，代表了基础和 临床研究人员，B）开发和支持正规的教育和培训计划， 在全国范围内传播充分利用这些新工具并将其区分开来所需的专业知识 人类细胞谱系的广泛多样性，c）维护和共享开源基因编辑工具 以及基因编辑的iPSC细胞系，这将使CTSA研究人员能够随意操纵人类基因组， 和d）从临床上最密集的细胞中产生的额外iPSC细胞系的国家共享的衍生 和遗传表型队列的个人目前在美国的今天：约6000 第二代和第三代的参与者。

Project Summary/Abstract The discovery of iPSCs provides an unprecedented opportunity for any scientist to derive an inexhaustible supply of patient-derived primary cells. These cells containing each patient's own genetic background can now be applied for in vitro human disease modeling, drug screening of personalized therapeutics, and the development of future regenerative cell-based therapies. The most valuable human clones already generated by the CTSA investigators collaborating on this proposal not only carry common disease-associated mutations and polymorphisms, but also carry knock-in fluorochrome reporters targeted to specific loci through state-of-the-art gene editing technologies. The goal of this proposal is the establishment of a CTSA network of induced pluripotent stem cell (iPSC) repositories and iPSC cores that will enable advanced disease modeling using >1000 existing normal and disease specific human cell lines and banking 6,000 additional samples procured from the 2nd and 3rd generation participants of the Framingham Study. A concerted effort for curation, sharing, and distribution of this vital resource across all CTSAs does not exist. This proposal thus creates a CTSA iPSC Network led by teams who have championed an `Open Source Biology' approach, freely sharing iPSC lines and their reprogramming reagents with more than 500 labs to date across the globe. Its goals are to make patient-derived iPSCs together with the tools and expertise for their genetic manipulation available to the greater research community on a large scale to realize their promise for extending understanding of disease and developing potential therapies. To achieve these goals, it proposes: a) national sharing of >1000 iPSC lines already derived by the CTSA teams collaborating in this proposal, representing a critical resource in high demand by both basic and clinical researchers, b) development and support of formalized education and training programs able to nationally disseminate the expertise required to fully harness these new tools and differentiate them into the wide diversity of human cell lineages, c) maintenance and sharing of open source gene-editing tools and gene edited iPSC lines that will enable CTSA investigators to manipulate the human genome at will, and d) derivation for national sharing of additional iPSC lines generated from the most densely clinically and genetically phenotyped cohort of individuals currently followed in the USA today: the ~6,000 participants of the second and third generations of the Framingham Study.