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
• 负责人: Paul Po Sheng cheng
• 金额: $ 6.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9609402
• 关键词: 15q22; Address; Affect; Anatomy; Arterial Fatty Streak; Atherosclerosis; Binding; Bioinformatics; Biologic Characteristic; Biological Process; Blood Vessels; Cardiovascular Diseases; Cell Count; Cell Differentiation process; Cell model; Cell physiology; Cells; Cellular biology; ChIP-seq; Computational Technique; Coronary Arteriosclerosis; Coronary artery; Coronary heart disease; Data; Data Set; Developmental Biology; Disease; Embryo; Embryonic Development; Enhancers; Fellowship; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Goals; Grant; Human; Lesion; Link; MADH3 gene; Mediating; Mentors; Modeling; Molecular; Mus; Pathway interactions; Phenotype; Physicians; Play; Population; Preventive; Process; Regulation; Risk; Risk Factors; Role; Scientist; Series; Signal Pathway; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; Stress; Therapeutic; Training; Transcriptional Regulation; Transforming Growth Factor beta; Variant; Work; career; disorder risk; experimental study; genome wide association study; genome-wide analysis; in vivo; innovation; mouse model; novel therapeutic intervention; novel therapeutics; progenitor; programs; response; risk variant; skills; stem cells; transcription factor; transcriptome; transcriptome sequencing

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 尽管疗法取得了重大进展，但冠状动脉疾病（CAD）仍然是美国的主要杀手， 全世界。识别危险因素并理解其潜在的生物学过程 需要开发创新的新疗法。许多遗传基因座与增加有关 基因组广泛关联研究（GWAS）中冠状动脉疾病（CAD）的风险。现在需要努力 识别这些基因座中的因果基因，并将其与特定的细胞过程和信号通路联系起来。 血管壁中的平滑肌细胞（SMC）表达大多数与CAD相关的基因 在GWAS。最近，SMAD3在15q22.33中被确定为CAD因果关系。发展 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 在血管应激的情况下，在血管壁中调制了SMC。这导致了我们的中心假设 SMAD3控制着一个转录网络，该网络抑制了针对保护性的SMC表型调制。 血管应激。本文描述的一系列实验旨在表征细胞机制 平滑肌SMAD3表达的哪种扰动可调节动脉粥样硬化病变，并识别 由SMAD3调节的遗传程序在人类冠状动脉平滑肌细胞中。 AIM 1利用 鼠动脉粥样硬化模型具有SMC特异性缺失的SMAD3和并发谱系跟踪。我们将 研究SMAD3表达对SMC细胞命运和由此产生的疾病解剖结构的影响。然后我们将申请 病变细胞的单细胞转录分析以检查不同SMC中的转录程序 后代，并将这些数据集结合在一起，以了解SMAD 3在SMC中介导的CAD风险是如何介导的 在细胞水平。 AIM 2应用人类冠状动脉平滑肌细胞模型来研究 通过SMAD3调节的转录程序，通过全基因组对增强子的识别 SMAD3及其转录调节作用。我们还将与来自另一个的数据重叠 平滑肌肉表达的CAD风险相关转录因子TCF21，以进一步了解我们对 调节CAD风险的SMC转录程序。这些研究将大大扩展我们 了解转录因子SMAD3和TCF21的作用，由SMC在CAD中表达，以及 显着提高了我们对因果变异介导CAD风险的机制的理解 未来引发新型治疗策略的希望。