Biorepository of Human iPSCs for Studying Dilated and Hypertrophic Cardiomyopathy

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。在此之前，由于获取人类心肌细胞的途径有限且难以培养，因此很难在人体模型中研究这些疾病。随着人类诱导多能干细胞（iPSCs）的发现，以及将其分化为跳动心肌细胞（iPSC-CMs）的效率和可重复性的提高，这一领域发生了巨大变化。现在首次有可能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。

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.