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
基本信息
- 批准号:10477676
- 负责人:
- 金额:$ 6.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:6p24AddressAwardBiologicalBlood VesselsCause of DeathCell modelCell physiologyCellsCessation of lifeClinicalCoronary ArteriosclerosisDiseaseDissectionEndothelin-1Functional disorderGenesGenetic RiskGenetic VariationHumanHuman GeneticsLinkMethodsMigraineOutcomePathway interactionsPatientsPopulation GeneticsPrevention strategyRiskStrokeTissuesTrainingUntranslated RNAVariantVascular Diseasescausal variantcell typedisabilitygenetic approachgenome editinggenome wide association studyinnovationnew therapeutic targetnovel strategiesnovel therapeuticspleiotropismsingle cell analysissingle-cell RNA sequencing
项目摘要
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共同导致超过一半的
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
6p 24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。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RAJAT M GUPTA的其他文献
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{{ truncateString('RAJAT M GUPTA', 18)}}的其他基金
Identifying the organotypic and disease-specific vascular cell populations by integrating single cell data with polygenic risk
通过将单细胞数据与多基因风险相结合来识别器官型和疾病特异性血管细胞群
- 批准号:
10652639 - 财政年份:2022
- 资助金额:
$ 6.83万 - 项目类别:
Identifying the organotypic and disease-specific vascular cell populations by integrating single cell data with polygenic risk
通过将单细胞数据与多基因风险相结合来识别器官型和疾病特异性血管细胞群
- 批准号:
10852399 - 财政年份:2022
- 资助金额:
$ 6.83万 - 项目类别:
Identifying the organotypic and disease-specific vascular cell populations by integrating single cell data with polygenic risk
通过将单细胞数据与多基因风险相结合来识别器官型和疾病特异性血管细胞群
- 批准号:
10530959 - 财政年份:2022
- 资助金额:
$ 6.83万 - 项目类别:
Single cell analysis of gene expression in human vascular cells
人类血管细胞基因表达的单细胞分析
- 批准号:
9810454 - 财政年份:2019
- 资助金额:
$ 6.83万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
9919442 - 财政年份:2019
- 资助金额:
$ 6.83万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
10004934 - 财政年份:2019
- 资助金额:
$ 6.83万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
9298804 - 财政年份:2016
- 资助金额:
$ 6.83万 - 项目类别:
From association to function at the PHACTR1 GWAS locus for coronary atherosclerosis
PHACTR1 GWAS 位点与冠状动脉粥样硬化的关联和功能
- 批准号:
9263835 - 财政年份:2016
- 资助金额:
$ 6.83万 - 项目类别:
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