Genetic and Stem Cell Model of Cardiac Metabolic Disease

项目摘要/摘要 2型糖尿病(T2D)是一种长期的代谢紊乱，影响着12%的美国人口。它是一家领先的 全国范围内的死亡原因，主要是由于相关的心血管疾病(心血管疾病，和GT；65%的患者)。 虽然心血管疾病的危险因素包括高胆固醇、高血压和吸烟，但部分患者患有 心肌功能障碍，一个被称为2型糖尿病心肌病(T2DCM)的术语，它暗示了 在心肌细胞内，可能会引起与糖尿病相关的有害心脏重塑。 尽管T2DCM的重要性显而易见，但目前还没有针对它的具体有效治疗方法，而且 在分子水平上对这种复杂的疾病缺乏深入的了解。因此，解决 T2DCM的作用机制是基础研究和翻译研究的迫切目标。最近的 出现新的技术突破，例如针对患者的人类诱导多能干细胞 (Ipscs)和基因组编辑，为研究基因之间的关联提供了前所未有的机会。 变异性和疾病易感性。我们的多PI R01授予的首要目标是了解 使用患者特异性IPSC来源的心肌细胞和内皮细胞进行T2DCM的潜在机制 并了解个体对疾病发展的易感性。我们已经集合好了 一支在心脏干细胞生物学、基因组学、分子生物学方面成就卓著的临床医生和研究人员团队 遗传学、生物统计学和生物信息学。我们有能力在五年内实现项目目标 好几年了。我们的建议将使一种新颖的个性化方法能够更好地理解机制 潜在的T2DCM，最终可能会使治疗策略发生革命性变化。

PROJECT SUMMARY/ABSTRACT Type 2 diabetes (T2D) is a long-term metabolic disorder affecting 12% of the US population. It is a leading cause of death nationwide, primarily due to associated cardiovascular disease (CVD, >65% of patients). While CVD risk factors include high cholesterol, hypertension, and smoking, a subset of patients suffer from myocardial dysfunction, a term named type 2 diabetic cardiomyopathy (T2DCM), which suggest factors within the cardiac myocyte itself may give rise to detrimental cardiac remodeling associated with diabetes. Despite the obvious importance of T2DCM, there is currently no specific effective treatment for it and a deep understanding of this complex disease at the molecular level is lacking. Hence, resolving the contributing mechanisms of T2DCM is a pressing goal of basic and translational research. The recent advent of new technological breakthroughs, such as patient-specific human induced pluripotent stem cells (iPSCs) and genome editing, provides an unprecedented opportunity to study associations between genetic variability and disease susceptibility. The overarching goal of our multi-PI R01 grant is to understand the underlying mechanisms of T2DCM using patient-specific iPSC-derived cardiomyocytes and endothelial cells from T2D patients and to understand individual susceptibility to disease development. We have assembled a team of highly accomplished clinicians and researchers in cardiac stem cell biology, genomics, molecular genetics, biostatistics and bioinformatics. We are well positioned to achieve the project goals within five years. Our proposal will enable a novel personalized approach to better understand the mechanisms underlying T2DCM that could ultimately revolutionize treatment strategies.