A genetic approach to identify the common mechanisms of vascular disease

项目摘要 在我的临床训练中，我反复看到血管疾病对心脏的破坏性影响。 病人在他们的生命中。冠状动脉疾病等血管疾病 (CAD)中风、动脉夹层和偏头痛联合收割机联合起来， 美国的死亡和残疾1。为了根除血管疾病， 重要的是要开发新的治疗方法， 开始.这些细胞中的致病途径可能是所有血管内皮细胞所共有的。 疾病及其共同的遗传风险可以成为了解这种病理生理学的一个窗口。的 与多种血管疾病相关的基因座最近已经通过 全基因组关联研究（GWAS）。这些位点代表了新的治疗靶点， 但它们的生物学机制仍在很大程度上尚未探索。存在多重挑战 来识别这些致病的生物机制。一是各 关联通常涉及多个变体。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，相关的细胞类型通常是 对于确定变体的功能至关重要。我发现了新的机会， 通过在GWAS分析、单细胞分析和细胞免疫分析中整合方法， 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表达的调节作用，并旨在扩展这一点。 独特的方法组合，以全套多效性血管位点。这个新 创新者奖申请旨在了解多个领域的交叉机制， 从功能上分析人类血管疾病的遗传变异。的解析 我建议的管道将优先考虑对三种血管疾病具有多效性效应的位点， 并探究它们对血管细胞功能的综合影响。我将建立一个分析 管道，以确定常见的血管疾病相关的基因座和功能 描述其生物学效应。这将确立一种新的确定优先次序的方法， 和功能表征的血管疾病引起的变种，并确定新的 治疗多种血管疾病的生物学途径。

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.