From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease

从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用

基本信息

  • 批准号:
    10241961
  • 负责人:
  • 金额:
    $ 16.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-20 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Coronary artery disease (CAD) remains the leading cause of death in the U.S. and worldwide. Identifying genetic risk factors and uncovering the underlying biological processes will lead to the development of much needed new avenues for therapies. Decades of genetics research, especially genome wide association studies (GWAS), have led to the discovery of numerous genetic loci associated with an increased risk for CAD. However, the majority of these loci lie in non-protein-coding regions. Efforts are needed to identify causal genes associated with these loci and the underlying cellular processes and signaling pathways. Recent advances in epigenomic and transcriptomic profiling at unprecedented depth and resolution, along with targeted genome/epigenome editing provide new opportunities to identify specific genes and cellular mechanisms in CAD. This K08 career development award is designed to launch the principal investigator’s career as an independent physician scientist that utilizes complementary computational and molecular approaches to discover the mechanisms that underlies human genetic risk to cardiovascular disease and translates these findings into treatment. The principal investigator ‘s Mentor (Thomas Quertermous) is a world leader in mechanistic studies of genetic risk of atherosclerosis. The proposed training is further supplemented by an advisory committee of leaders in computational biology, genetics, and single-cell multi-omic analysis, including Michael Snyder, Erik Ingelsson, William Greenleef, and Siddhartha Jaiswal, along with formal didactic courses at Stanford University and Cold Spring Harbor. Funded by an F32, the principle investigator used a combination of in vitro and in vivo models of atherosclerosis and linked the non-coding CAD risk loci at 2q22 to ZEB2, a transcriptional repressor with a critical role in cell-state transitions. ZEB2 appears to be specifically up-regulated in phenotypically modulated smooth muscle cells (SMC) in atherosclerotic lesions, and modulates their cell-fate decisions. The proposed study will: (1) identify the causal regulatory element(s) responsible for the CAD-Risk-associated region at 2q22; (2) reveal the molecular mechanisms by which ZEB2 affects phenotypic modulation of SMC; (3) determine the cellular mechanism by which perturbation of smooth muscle cell Zeb2 expression modulates atherosclerotic lesions in vivo. The result of this study will elucidate new regulatory mechanisms that modulate atherosclerosis biology. Additionally, the principle investigator will gain the training needed to transition into an independent physician scientist focusing on translating genetic findings of human cardiovascular disease into specific mechanisms and novel therapies.
摘要

项目成果

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Paul Po Sheng cheng其他文献

Paul Po Sheng cheng的其他文献

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{{ truncateString('Paul Po Sheng cheng', 18)}}的其他基金

From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
  • 批准号:
    10666553
  • 财政年份:
    2020
  • 资助金额:
    $ 16.65万
  • 项目类别:
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
  • 批准号:
    10469431
  • 财政年份:
    2020
  • 资助金额:
    $ 16.65万
  • 项目类别:
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
  • 批准号:
    10900886
  • 财政年份:
    2020
  • 资助金额:
    $ 16.65万
  • 项目类别:
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
  • 批准号:
    10038543
  • 财政年份:
    2020
  • 资助金额:
    $ 16.65万
  • 项目类别:
The molecular mechanisms of SMAD3-mediated coronary disease risk
SMAD3介导的冠心病风险的分子机制
  • 批准号:
    9609402
  • 财政年份:
    2018
  • 资助金额:
    $ 16.65万
  • 项目类别:

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