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 先天性听觉疾病（CHD）是美国死亡的主要原因。 尽管遗传因素对CVD有很大的贡献，但对 这些疾病的根本遗传原因。我们已经开始了高吞吐量 测序和高吞吐量在体内表征CVD基因的基因表征 离群值和亲属工会的后代。使用全外观 从链接到基因集的测序（WES）和最新分析方法的状态 富集分析，我们已经确定了基于CAD的独立突变， 代谢综合征和多样化的冠心。我们在鉴定疾病基因的成功是 部分原因是世界各地的独特疾病人群以及 耶鲁大学孟德尔基因组学中心。当我们设计了创造性的方法时 新颖的基因发现，我们实验室的独特特征是追求 体内疾病基因的表征及其在鉴定新疾病方面的成功 药物开发的途径和目标。我们已经建立了高吞吐量 实验室中的技术，用于体外鉴定的人类突变的功能表征 并通过采用新型基因编辑技术来体内。最近，我们已经开始 研究衰老，饮食和体育锻炼对疾病的表观遗传作用 人和动物模型中的发病机理。最值得注意的是，我们迈出了进一步 并已与行业开始合作，以进行筛查和 表征可以针对已识别疾病途径的小分子 救援心血管和代谢特征。我们高度引用的发表作品是证明 对于我们在实验室中产生的结果的质量和有希望的性质。