Genetic and Stem Cell Model of Cardiac Metabolic Disease

心脏代谢疾病的遗传和干细胞模型

基本信息

批准号：
9893900
负责人：
THOMAS QUERTERMOUS
金额：
$ 75.09万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893900
关键词：
Affect Autophagocytosis Basic Science Bioinformatics Biometry CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell Line Cholesterol Clinic Clinical Clinical Research Complex Coronary Arteriosclerosis DNA Data Defect Development Diabetes Mellitus Disease Disease susceptibility Endocrinology Endothelial Cells Endothelium Enrollment Evolution Exhibits Exposure to Functional disorder Genes Genetic Genomics Genotype Goals Grant Human Hyperglycemia Hypertension Impairment Individual Interdisciplinary Study Left Left Ventricular Ejection Fraction Metabolic Metabolic Diseases Mitochondria Modeling Molecular Molecular Genetics Molecular Profiling Myocardial dysfunction Names Non-Insulin-Dependent Diabetes Mellitus Patients Physical activity Population Positioning Attribute Predisposition Relaxation Research Personnel Risk Risk Factors Sampling Selection Criteria Single Nucleotide Polymorphism Smoking Structure Susceptibility Gene Training Programs Translational Research Type 2 diabetic Ventricular base cardiometabolism cardiovascular disorder risk design diabetic diabetic cardiomyopathy diabetic patient disease phenotype effective therapy ethnic diversity gender diversity genetic information genome editing genome sequencing genomic data high risk induced pluripotent stem cell insight molecular phenotype novel patient subsets personalized approach precision genetics pressure randomized trial recruit response stem cell biology stem cell model targeted treatment transcriptome sequencing treatment strategy whole genome

项目摘要

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.

项目摘要/摘要 2型糖尿病（T2D）是一种影响美国人群12％的长期代谢疾病。这是领先全国死亡原因，主要是由于相关的心血管疾病（CVD，> 65％的患者）。 CVD危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障碍，一个名为2型糖尿病心肌病（T2DCM）的术语，提出了因素心肌细胞本身可能导致与糖尿病相关的有害心脏重塑。尽管T2DCM显而易见，但目前尚无针对它的特定有效治疗方法缺乏对分子水平上这种复杂疾病的深刻理解。因此，解决 T2DCM的贡献机制是基础研究和转化研究的紧迫目标。最近新技术突破的出现，例如特定于患者的人类诱导多能干细胞（IPSC）和基因组编辑，为研究遗传之间的关联提供了前所未有的机会变异性和疾病易感性。我们多PI R01赠款的总体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T2DCM的基本机制来自T2D患者，了解个人对疾病发展的敏感性。我们已经组装了一支高度成就的临床医生和心脏干细胞生物学，基因组学，分子的研究人员遗传学，生物统计学和生物信息学。我们在五个之内实现项目目标的好处年。我们的建议将使一种新颖的个性化方法更好地了解机制最终可能彻底改变治疗策略的基础T2DCM。