Biorepository of Human iPSCs for Studying Dilated and Hypertrophic Cardiomyopathy

描述（由申请人提供）：家族性扩张型心肌病（DCM）和家族性肥厚型心肌病（HOM）被认为是遗传性心血管疾病的两种最常见原因。以前，由于人类心肌细胞的获取有限且难以生长，因此很难在人类模型中研究这些疾病。随着人类诱导多能干细胞（iPSC）的发现以及将其分化为搏动心肌细胞（iPSC-CM）的效率和可重复性的提高，情况发生了巨大变化。这是第一次，现在可以创建患者特异性和疾病特异性细胞系，以提高我们对DCM和HCM分子机制的理解。 因此，这个多学科R24资源相关研究项目的主要目标是（i）产生，（ii）表征，（iii）测序和（iv）心脏iPSC系的分布。在接下来的5年里，我们计划建立一个包含600个来自对照个体、HCM患者和DCM患者的iPSC细胞系的库。为了实现这些目标，我们组建了一支真正的合作团队，由心血管医学，iPSC生物学，发育生物学，下一代测序（NGS）技术，群体遗传学，生物医学信息学，大规模数据库存储库和业务开发方面的专业知识组成。我们在未来五年提出以下四个具体目标： 目的1：从对照、DCM和HCM患者产生600个iPSC系。 目的2：评估使用iPSC的药物安全性筛选（“培养皿中的临床试验”）。 目的3：利用DNA-seq和RNA-seq技术获得基因型-表型信息。 目的4：向学术界提供IPSC品系及其基因型-表型数据。 总之，我们相信这个R24将满足国家的需求，并实现NHLBI的战略愿景，即创造一种对更广泛的科学界有价值的新型生物储存库（iPSC-基因型-表型）。鉴于我们的专业知识和往绩记录，我们有信心能够实现这些里程碑。

DESCRIPTION (provided by applicant): Familial dilated cardiomyopathy (DCM) and familial hypertrophic cardiomyopathy (HOM) are considered the two most common causes of inherited cardiovascular diseases. Previously, it has been difficult to study these diseases in human models because of limited access to human cardiomyocytes and difficulty growing them. With the discovery of human induced pluripotent stem cells (iPSCs) and the increased efficiency and reproducibility of differentiating them into beating cardiomyocytes (iPSC-CMs), the landscape has dramatically changed. For the first time, it is now possible to create patient-specific and disease-specific cell lines to improve our understanding of the molecular mechanisms of DCM and HCM. Hence the major goals of this multidisciplinary R24 Resource-Related Research Project are (i) generation, (ii) characterization, (iii) sequencing, and (iv) distribution of cardiac iPSC lines. Over the next 5 years, we plan to create an iPSC bank of 600 lines derived from control individuals, HCM patients, and DCM patients. To accomplish these goals, we have assembled a truly collaborative team of investigators with expertise in cardiovascular medicine, iPSC biology, developmental biology, next generation sequencing (NGS) technology, population genetics, biomedical informatics, large-scale database repository, and business development. We propose the following 4 Specific Aims over the next 5 years: Aim 1: To generate 600 iPSC lines from controls, DCM, and HCM patients. Aim 2: To evaluate drug safety screening using iPSCs ("clinical trial in a petri dish"). Aim 3: To obtain genotype-phenotype information using DNA-seq and RNA-seq. Aim 4: To distribute IPSC lines and their genotype-phenotype data to academic community. In summary, we believe this R24 will address a national need and fulfill NHLBI's strategic vision of creating a novel biorepository (iPSC-genotype-phenotype) that is valuable to the broader scientific community. Given our expertise and track record, we are confident we can deliver on these milestones.