Biorepository of Human iPSCs for Studying Dilated and Hypertrophic Cardiomyopathy

描述(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个最常见的原因。此前，在人体模型中研究这些疾病一直很困难，因为获得人类心肌细胞的途径有限，而且难以培养它们。随着人类诱导多能干细胞(IPSCs)的发现以及将其分化为搏动心肌细胞(IPSC-CMS)的效率和重复性的提高，这种情况发生了戏剧性的变化。现在，首次有可能建立患者特异性和疾病特异性细胞系，以提高我们对扩张型心肌病和肥厚型心肌病分子机制的理解。 因此，这一多学科的R24资源相关研究项目的主要目标是(I)产生、(Ii)鉴定、(Iii)测序和(Iv)心脏IPSC系的分布。在接下来的5年里，我们计划创建一个包含600个来自对照组、肥厚型心肌炎患者和扩张型心肌炎患者的IPSC库。为了实现这些目标，我们组建了一支真正合作的研究团队，他们拥有心血管医学、IPSC生物学、发育生物学、下一代测序(NGS)技术、人口遗传学、生物医学信息学、大型数据库存储库和业务开发方面的专业知识。我们提出了未来5年的4个具体目标： 目的1：从对照组、扩张型心肌病和肥厚型心肌病患者中获得600株IPSC。 目的：评价IPSCs(“培养皿临床试验”)的药物安全性筛选。 目的3：利用DNA-seq和RNA-seq获得基因-表型信息。 目的4：向学术界分发IPSC株系及其基因-表型数据。 总而言之，我们相信R24将满足国家需求，并实现NHLBI创建对更广泛的科学界有价值的新生物库(IPSC-基因-表型)的战略愿景。鉴于我们的专业知识和过往记录，我们有信心实现这些里程碑。

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.