A genetic approach to identify the common mechanisms of vascular disease

识别血管疾病常见机制的遗传学方法

• 批准号: 10477676
• 负责人: RAJAT M GUPTA
• 金额: $ 6.83万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477676
• 关键词: 6p24; Address; Award; Biological; Blood Vessels; Cause of Death; Cell model; Cell physiology; Cells; Cessation of life; Clinical; Coronary Arteriosclerosis; Disease; Dissection; Endothelin-1; Functional disorder; Genes; Genetic Risk; Genetic Variation; Human; Human Genetics; Link; Methods; Migraine; Outcome; Pathway interactions; Patients; Population Genetics; Prevention strategy; Risk; Stroke; Tissues; Training; Untranslated RNA; Variant; Vascular Diseases; causal variant; cell type; disability; genetic approach; genome editing; genome wide association study; innovation; new therapeutic target; novel strategies; novel therapeutics; pleiotropism; single cell analysis; single-cell RNA sequencing

Project Summary In my clinical training, I repeatedly saw the devastating effects of vascular disease on patients in the prime of their lives. Vascular diseases such as coronary artery disease (CAD), stroke, arterial dissection, and migraine headache combine to cause over half the death and disability in the United States1. To eradicate vascular disease it will be important to develop new treatments that target the arterial cells where the disease begins. The disease-causing pathways in these cells may be common to all vascular diseases, and their shared genetic risk can be a window into this pathophysiology. The loci associated with multiple vascular diseases have recently been identified through genome-wide association studies (GWAS). These loci represent new therapeutic targets, but their biological mechanisms remain largely unexplored. There are multiple challenges that exist for identifying these disease-causing biological mechanisms. First, each association often involves multiple variants. Second, most causal variants occur in non- coding regions, where the associated gene is unclear. Third, the relevant cell type is often critical for determining the function of a variant. I have identified new opportunities to address each of these challenges by integrating methods in GWAS analysis, single cell RNA-sequencing, and genome-editing of vascular cells. I utilized this approach to study the regulatory effect of the 6p24 locus on endothelin-1 expression, and aim to extend this unique combination of methods to the full set of pleiotropic vascular loci. This New Innovator Award application seeks to understand the intersecting mechanisms of multiple vascular diseases from the functional analysis of human genetic variation. The analytic pipeline I propose will prioritize loci with pleiotropic effects on three vascular diseases, and interrogate their combined effects on vascular cell function. I will establish an analytic pipeline to identify common vascular disease-associated loci and functionally characterize their biological effects. This will establish a new approach to the prioritization and functional characterization of vascular disease-causing variants, and identify new biological pathways for the treatment of multiple vascular diseases.

项目摘要 在我的临床训练中，我反复看到血管疾病对 病人们正处于他们的壮年时期。血管疾病，如冠状动脉疾病 (CAD)、中风、动脉夹层和偏头痛加在一起导致了超过一半的 美国的死亡和残疾1。要根除血管疾病，将是 重要的是要开发新的治疗方法，针对疾病所在的动脉细胞 开始。这些细胞的致病途径可能是所有血管的共同之处。 疾病及其共同的遗传风险可以成为了解这一病理生理学的窗口。这个 与多种血管疾病相关的基因座最近通过 全基因组关联研究(GWAS)。这些基因座代表了新的治疗靶点， 但它们的生物学机制在很大程度上仍未被探索。这是一个多重挑战 以确定这些致病的生物机制。首先，每个人 关联通常涉及多个变种。其次，大多数因果变异发生在非 编码区，其中相关基因尚不清楚。第三，相关单元格类型通常是 对确定变体的功能至关重要。我已经找到了新的机会来 通过将方法集成到GWAS分析中，解决这些挑战中的每一个 血管细胞的RNA测序和基因组编辑。我利用这种方法来研究 6p24基因座对内皮素-1表达的调控作用 独特的方法组合，以获得全套多效性血管基因座。这条新闻 创新者奖申请旨在了解多个 血管疾病从功能上分析人类的遗传变异。分析性的 我建议的管道将优先考虑对三种血管疾病具有多效性的基因座， 并询问它们对血管细胞功能的联合影响。我会建立一个分析 识别常见血管疾病相关基因和功能的管道 描述它们的生物学效应。这将建立一种确定优先顺序的新方法 和导致血管疾病的变异的功能特征，并识别新的 治疗多种血管疾病的生物途径。