The molecular mechanisms of SMAD3-mediated coronary disease risk

SMAD3介导的冠心病风险的分子机制

基本信息

  • 批准号:
    9609402
  • 负责人:
  • 金额:
    $ 6.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-15 至 2021-09-14
  • 项目状态:
    已结题

项目摘要

Project Summary Despite major advances in therapies, coronary artery disease (CAD) remains the leading killer in the US and worldwide. Identification of risk factors and understanding their underlying biological processes are urgently needed to develop innovative new therapies. Numerous genetic loci have been associated with an increased risk for coronary artery disease (CAD) in genome wide association studies (GWAS). Now efforts are needed to identify causal genes in these loci and link them to specific cellular processes and signaling pathways. Smooth muscle cells (SMC) in the vascular wall express a majority of CAD-associated genes identified in GWAS. Recently, SMAD3 has been identified as the CAD causal association at 15q22.33. Developmental biology as well as our preliminary data suggest SMAD3 may modify cell-fate decisions of phenotypically modulated SMC in the vascular walls in the setting of vascular stress. This led to our central hypothesis that SMAD3 governs a transcriptional network that inhibits protective SMC phenotypic modulation in response to vascular stress. The series of experiments described herein aim to characterize the cellular mechanisms by which perturbation of smooth muscle Smad3 expression modulates atherosclerotic lesions, as well as identify the genetic program regulated by SMAD3 in human coronary artery smooth muscle cells. Aim 1 utilizes a murine atherosclerosis model with SMC-specific deletion of Smad3 and concurrent lineage tracing. We will investigate the effect of Smad3 expression on SMC cell fate and resulting disease anatomy. We will then apply single cell transcriptional profiling of lesion cells to examine the transcriptional program in different SMC progenies, and combine these datasets to understand how CAD risk is mediated by Smad3 specifically in SMC at the cellular level. Aim 2 applies a human coronary artery smooth muscle cell model to study the transcriptional program regulated by SMAD3 through genome-wide identification of enhancers bound by SMAD3 and their transcriptional regulatory effects. We will also overlap the finding with data from another smooth-muscle-expressed CAD-risk-associated transcription factor TCF21, to further our understanding of the SMC transcriptional program that regulates CAD risk. Together, these studies will significantly expand our understanding of the role of transcription factors SMAD3 and TCF21 expressed by SMCs in CAD, and significantly advance our understanding of mechanisms by which causal variation mediates risk for CAD with the hope of leading to novel therapeutic strategies in the future.
项目摘要 尽管在治疗方面取得了重大进展,但冠状动脉疾病(CAD)仍然是美国的主要杀手, 国际吧识别风险因素并了解其潜在的生物过程是迫切需要的。 需要开发创新的新疗法。许多遗传位点与增加的 冠状动脉疾病(CAD)的风险在全基因组关联研究(GWAS)。现在需要努力 确定这些基因座中的致病基因,并将它们与特定的细胞过程和信号通路联系起来。 血管壁的平滑肌细胞(SMC)表达大多数CAD相关基因 在GWAS。最近,SMAD3已被确定为15q22.33处的CAD因果关联。发育 生物学以及我们的初步数据表明,SMAD3可能会改变表型的细胞命运决定, 在血管应力的情况下调节血管壁中的SMC。这导致了我们的核心假设, SMAD3控制转录网络,抑制保护性SMC表型调节, 血管应力本文所述的一系列实验旨在通过以下方式表征细胞机制: 平滑肌Smad3表达的扰动调节动脉粥样硬化病变,以及鉴定 人冠状动脉平滑肌细胞中SMAD3调控的遗传程序。目标1利用了 具有SMC特异性Smad3缺失和同时谱系追踪的小鼠动脉粥样硬化模型。我们将 研究Smad3表达对SMC细胞命运和导致的疾病解剖的影响。然后我们将申请 损伤细胞的单细胞转录谱分析,以检查不同SMC中的转录程序 后代,并联合收割机这些数据集,以了解如何CAD风险是由Smad3介导的,特别是在SMC 在细胞水平上。目的2应用人冠状动脉平滑肌细胞模型, 通过全基因组鉴定SMAD3结合的增强子来调控转录程序 SMAD3及其转录调控作用。我们还将把这一发现与另一项研究的数据重叠起来。 平滑肌表达的CAD风险相关转录因子TCF 21,以进一步了解 调节CAD风险的SMC转录程序。总之,这些研究将大大扩大我们的 了解SMC表达的转录因子SMAD 3和TCF 21在CAD中的作用, 显著提高了我们对因果变异介导CAD风险机制的理解, 希望能在未来带来新的治疗策略。

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:
    $ 6.6万
  • 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:
    10241961
  • 财政年份:
    2020
  • 资助金额:
    $ 6.6万
  • 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:
    $ 6.6万
  • 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:
    $ 6.6万
  • 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:
    $ 6.6万
  • 项目类别:

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