The Identification and characterization of genetic variants underlying cardiovascular diseases

心血管疾病遗传变异的鉴定和表征

• 批准号: 9243632
• 负责人: Arya Mani
• 金额: $ 100.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-23 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243632
• 关键词: Animal Model; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Coronary Arteriosclerosis; Diet; Disease; Disease Pathway; Disease model; Drug Targeting; Epigenetic Process; Genes; Genetic; Genomics; Hearing problem; High-Throughput Nucleotide Sequencing; Human; In Vitro; Industry; Laboratories; Metabolic; Metabolic syndrome; Mutation; Nature; Pathogenesis; Physical activity; Population; Publishing; Techniques; United States; Work; age effect; drug development; exome sequencing; gene discovery; genetic variant; in vivo; invention; kindred; novel; novel strategies; offspring; prevent; small molecule; success; trait

Cardiovascular disorders (CVD), including coronary artery disease (CAD) and congenital hear diseases (CHD) are the leading causes of death in the United States. Despite strong contribution of genetic factors to CVD, very little is known about the underlying genetic causes of these diseases. We have embarked on high throughput sequencing and high throughput in vivo characterization of genes underlying CVD in outlier kindreds and in offsprings of consanguineous unions. Using whole-exome sequencing (WES) and state of the art analytic approaches, from linkage to gene set enrichment analysis, we have identified independent mutations that underlie CAD, metabolic syndrome and diverse CHD. Our success in identification of disease genes is in part due to access to unique disease populations across the world and the support of Yale Center for Mendelian Genomics. While we have devised inventive approaches for novel gene discovery, the distinctive feature of our laboratory is in pursuing the characterization of disease genes in vivo and its success in identifying novel disease pathways and targets for drug development. We have established high throughput techniques in the lab for functional characterization of identified human mutations in vitro and in vivo by employing novel gene editing techniques. Most recently, we have begun to investigate the epigenetic effects of aging, diet and physical activity on disease pathogenesis in human and animal models. Most notably, we have taken a step further and have initiated collaborative efforts with the industry in order to screen and characterize small molecules that can target identified disease pathways in order to rescue cardiovascular and metabolic traits. Our highly cited published work is an attest for the quality and the promising nature of the results we generate in the lab.

心血管疾病（CVD），包括冠状动脉疾病（CAD）和