Genetic and Stem Cell Model of Cardiac Metabolic Disease

项目总结/摘要 2型糖尿病（T2 D）是一种长期代谢紊乱，影响12%的美国人口。它是最主要的 死亡原因，主要是由于相关的心血管疾病（CVD，>65%的患者）。 虽然CVD风险因素包括高胆固醇、高血压和吸烟，但一部分患者患有 心肌功能不全，称为2型糖尿病心肌病（T2 DCM），这表明 在心肌细胞内的这种改变本身可能引起与糖尿病相关的有害的心脏重塑。 尽管T2 DCM的重要性显而易见，但目前还没有特异性有效的治疗方法， 对这种复杂疾病缺乏分子水平的深入了解。因此，解决 T2 DCM的作用机制是基础和转化研究的迫切目标。近期 新技术突破的出现，如患者特异性人类诱导多能干细胞 （iPSCs）和基因组编辑，提供了一个前所未有的机会，研究遗传之间的关联 变异性和疾病易感性。我们的多PI R 01赠款的首要目标是了解 使用患者特异性iPSC衍生的心肌细胞和内皮细胞的T2 DCM的潜在机制 从T2 D患者和了解个体对疾病发展的易感性。我们已经组建 一个由在心脏干细胞生物学、基因组学、分子生物学、 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。 年我们的建议将使一种新颖的个性化方法，以更好地了解机制 潜在的T2 DCM可能最终彻底改变治疗策略。

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.