Human Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling

描述（由申请人提供）：从体细胞成功衍生人诱导多能干细胞（hiPSC）为克服心血管疾病领域的障碍提供了巨大潜力。hiPSC衍生的心脏细胞现在可以为体外疾病建模和体内再生医学治疗提供令人难以置信的潜力。最近，已经发表了几个令人兴奋的hiPSC衍生的心脏细胞的疾病建模能力的证明（例如，Timothy综合征、LEOPARD综合征）。已发现这些患者特异性hiPSC-CM概括了疾病表型。与Timothy和LEOPARD综合征（被认为是孤儿病）相比，家族性扩张型心肌病（DCM）是心力衰竭的最常见原因，因此给美国和全球的医疗保健系统带来了巨大负担。在这里，我们试图从家族性扩张型心肌病患者中获得hiPSC（目标1），确定DCM患者与健康对照的hiPSC-心脏细胞的表型（目标2），并在使用同源重组进行遗传拯救后评估其功能（目标3）。我们相信这些发现对更好地理解扩张型心肌病的分子和细胞基础具有广泛的临床和科学影响。 公共卫生相关性：家族性扩张型心肌病（DCM）是心力衰竭的最常见原因，给美国和全球的医疗保健系统带来了巨大的负担。从基因组时代的早期开始，自从描述了第一个家族性DCM引起的突变，研究人员试图通过将基因型与临床表型表达相关联来研究其机制基础。不幸的是，这些研究由于无法接近人类心肌细胞而受到严重阻碍。在这项拨款提案中，我们将从DCM患者中产生人类诱导多能干细胞衍生的心肌细胞（hiPSC-CM）。我们将进行详细的机制分析，以确定DCM的功能和分子表型。这种方法将大大提高我们进行未来高通量药物筛选，评估基因和细胞疗法，并评估潜在的DCM新疗法的能力。

DESCRIPTION (provided by applicant): The successful derivation of human induced pluripotent stem cells (hiPSCs) from somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC-derived cardiac cells can now provide incredible potential for disease modeling in vitro and regenerative medicine therapies in vivo. Recently, several exciting demonstrations of the disease modeling capability of hiPSC- derived cardiac cells have been published (e.g., Timothy syndrome, LEOPARD syndrome). These patient-specific hiPSC-CMs have been found to recapitulate the disease phenotypes. In contrast to Timothy and LEOPARD syndrome (which are considered orphan diseases), familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and hence places a tremendous burden on the healthcare system in the US and worldwide. Here we seek to derive hiPSCs from patients with familial dilated cardiomyopathy (Aim 1), determine the phenotype of hiPSC-cardiac cells from DCM patients versus healthy controls (Aim 2), and evaluate their functionality after genetic rescue using homologous recombination (Aim 3). We believe the findings here should have broad clinical and scientific impact toward better understanding on the molecular and cellular basis of DCM. PUBLIC HEALTH RELEVANCE: Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and places a tremendous burden on the healthcare system in the US and worldwide. From the early beginnings of the genomic era and since the description of the first familial DCM causing mutations, investigators have attempted to study its mechanistic basis by correlating genotype with clinical phenotype expression. Unfortunately, these studies have been severely hampered by the inaccessibility of human cardiomyocytes. In this grant proposal, we will generate human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with DCM. We will perform detailed and mechanistic analyses to determine the functional and molecular phenotypes of DCM. This approach will dramatically enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of DCM.