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.

项目概要/摘要 2 型糖尿病 (T2D) 是一种长期代谢性疾病，影响着 12% 的美国人口。它是一个领先的全国范围内的死亡原因，主要是由于相关心血管疾病（CVD，> 65% 的患者）。虽然 CVD 危险因素包括高胆固醇、高血压和吸烟，但一部分患者患有以下疾病心肌功能障碍，一个称为 2 型糖尿病心肌病 (T2DCM) 的术语，表明有以下因素心肌细胞本身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，但目前尚无具体有效的治疗方法，且尚无有效的治疗方法。目前缺乏对这种复杂疾病在分子水平上的深入了解。因此，解决 T2DCM 的贡献机制是基础和转化研究的紧迫目标。最近的新技术突破的出现，例如患者特异性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。我们的多 PI R01 资助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进行 T2DCM 的潜在机制来自 T2D 患者并了解个体对疾病发展的易感性。我们已经集合了一支由心脏干细胞生物学、基因组学、分子生物学领域卓有成就的临床医生和研究人员组成的团队遗传学、生物统计学和生物信息学。我们完全有能力在五年内实现项目目标年。我们的建议将提供一种新颖的个性化方法来更好地理解这些机制潜在的 T2DCM 最终可能彻底改变治疗策略。