NATIONAL BIOREPOSITORY OF LUNG DISEASE-SPECIFIC HUMAN INDUCED PLURIPOTENT STEM CELLS:THE PURPOSE OF THIS RESOURCE IS TO BUILD AND SUPPORT A CRITICAL

摘要 这项提议旨在支持为肺病研究人员提供正式的国家资源，包括可以不受限制或排他性地共享的肺部疾病特异性诱导多能干细胞(IPSC)生物库。超过200个与人类肺部疾病相关的IPSC系及其基因编辑的后代现在被储存在波士顿大学/波士顿医学中心的再生医学中心(CReM)，为任何基础科学家提供了一个前所未有的机会来获得取之不尽的患者来源的肺上皮细胞、血管细胞、免疫细胞或间质细胞。这些包含每个患者自己的遗传背景的细胞现在可用于体外人类肺部疾病建模、个性化治疗的药物筛选以及未来基于肺再生细胞的治疗的开发。这个库中最有价值的人类克隆不仅携带最常见的肺部疾病诱发突变(例如，编码CFTR、Alpha-1抗胰蛋白酶、BMPR2、SFTPC、SFTPB、ABCA3和Nkx2.1的基因座突变)，而且还通过最先进的基因编辑技术携带针对特定基因座的敲入荧光记者。我们建议通过正式机制向所有研究人员提供生物库，以确保：a)国家共享IPSCs， 包括基础和临床肺病研究人员迫切需要的关键资源；b)建立质量保证途径和方法，用于银行、管理和维护携带大多数美国肺病研究人员在未来几年所需的最常见基因突变和肺谱系报告基因的详尽的人类品系小组；以及c)继续正式的教育和培训计划，能够在全国范围内传播充分利用这些新工具并将其区分为肺谱系所需的专业知识。

ABSTRACT This proposal seeks to support a formalized national resource for lung researchers consisting of a lung disease specific induced pluripotent stem cell (iPSC) biorepository that can be shared without restriction or exclusivity. More than 200 human lung disease-relevant iPSC lines, and their gene-edited progeny, are now banked in the Center for Regenerative Medicine (CReM) of Boston University/Boston Medical Center, providing an unprecedented opportunity for any basic scientist to derive an inexhaustible supply of patient-derived lung epithelial, vascular, immune, or interstitial cells. These cells containing each patient’s own genetic background are now available for in vitro human lung disease modeling, drug screening of personalized therapeutics, and the development of future lung regeneration cell-based therapies. The most valuable human clones in this bank not only carry the most common lung disease-inducing mutations (e.g. mutations in loci encoding CFTR, Alpha-1 antitrypsin, BMPR2, SFTPC, SFTPB, ABCA3, and NKX2.1), but also carry knock-in fluorochrome reporters targeted to specific loci through state-of-the-art gene editing technologies. We propose to make the biorepository available to all researchers through formalized mechanisms that ensure: a) national sharing of iPSCs that comprise a critical resource in high demand by both basic and clinical lung researchers, b) establishment of quality assurance approaches and methods for banking, curating, and maintaining an exhaustive panel of human lines carrying the most common gene mutations and lung lineage reporter genes required by the majority of U.S. lung researchers in the years ahead, and c) continuation of a formalized education and training program able to nationally disseminate the expertise required to fully harness these new tools and differentiate them into lung lineages.