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，我一再看到血管疾病对 患者一生。血管疾病，例如冠状动脉疾病 （CAD），中风，动脉解剖和偏头痛，结合了一半以上 美国的死亡与残疾1。为了消除血管疾病，这将是 开发针对该疾病的动脉细胞的新疗法很重要 开始。这些细胞中引起疾病​​的途径可能是所有血管的共同点 疾病及其共同的遗传风险可能是进入这种病理生理学的窗口。这 最近通过 全基因组关联研究（GWAS）。这些基因座代表新的治疗靶标， 但是它们的生物学机制在很大程度上尚未探索。有很多挑战 为了识别这些引起疾病的生物学机制而存在。首先，每个 关联通常涉及多种变体。其次，大多数因果变异发生在非 - 编码区，相关基因不清楚。第三，相关的单元格通常是 对于确定变体的功能至关重要。我已经确定了新的机会 通过将方法整合在GWAS分析中，单个单元格中，解决这些挑战中的每一个 RNA测序和血管细胞的基因组编辑。我利用这种方法来学习 6p24基因座对内皮素-1表达的调节作用，并旨在扩展这一点 整个多效性血管基因座的方法的独特组合。这个新 创新者奖申请旨在了解多重的相交机制 来自人类遗传变异的功能分析的血管疾病。分析 我建议的管道将优先考虑对三种血管疾病的多效影响的基因座， 并询问其对血管细胞功能的综合作用。我将建立一个分析 识别常见血管疾病相关的基因座的管道和功能 表征它们的生物学作用。这将建立新的优先级方法 以及引起血管疾病变体的功能表征，并确定新的 治疗多种血管疾病的生物学途径。