A National iPS Cell Network with Deep Phenotyping for Translational Research

项目摘要/摘要 IPSCs的发现为任何科学家提供了一个前所未有的机会来推导出 取之不尽的病人来源的原代细胞。这些细胞包含每个患者自己的基因 背景技术现可应用于人体疾病的体外建模、个体化药物筛选 治疗学，以及未来再生细胞疗法的发展。最有价值的人 CTSA调查人员就这一提议进行合作已经生成的克隆不仅具有共同的 与疾病相关的突变和多态，还携带敲入荧光染料的记者 通过最先进的基因编辑技术针对特定的基因座。这项提议的目标是 诱导多能干细胞库CTSA网络的建立和 IPSC核心，将使用&gt；1000现有的正常和疾病实现高级疾病建模 特定的人类细胞系和从第2和第3批获得的额外6,000份样本 弗雷明翰研究的一代参与者。 协调努力在所有CTSA之间管理、共享和分配这一重要资源并不意味着 是存在的。因此，这项提议创建了一个CTSA IPSC网络，由支持开放的团队领导 源生物学的方法，免费共享iPSC系及其重编程试剂与超过 迄今为止，全球已有500个实验室。它的目标是与这些工具一起制造患者衍生的ipscs 以及他们的基因操作方面的专业知识，可供更大规模的研究界使用 以实现他们对扩大对疾病的理解和开发潜在治疗方法的承诺。至 为了实现这些目标，它建议：a)在全国范围内共享CTSA已经派生的&gt；1000条iPSC生产线 在此提案中协作的团队，代表着基础和基础资源的高需求 临床研究人员，b)制定和支持正规教育和培训方案，能够 在全国范围内传播充分利用这些新工具所需的专业知识，并将它们区分为 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株系，将使CTSA调查人员能够随意操纵人类基因组， 和d)从临床上最密集的 目前在美国关注的遗传表型个体队列：约6,000人 弗雷明翰研究的第二代和第三代参与者。

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.