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.

项目概要 尽管治疗方法取得了重大进展，但冠状动脉疾病 (CAD) 仍然是美国的头号杀手 全世界。识别风险因素并了解其潜在的生物过程刻不容缓 需要开发创新的新疗法。许多遗传位点与增加 全基因组关联研究（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它们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) 表达大多数已确定的 CAD 相关基因 在 GWAS 中。最近，SMAD3 已被确定为 15q22.33 的 CAD 因果关联。发育性 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调节血管壁中的 SMC。这导致我们的中心假设是 SMAD3 控制转录网络，抑制保护性 SMC 表型调节以响应 血管应激。本文描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 表达的扰动可调节动脉粥样硬化病变，并确定 人类冠状动脉平滑肌细胞中由 SMAD3 调节的遗传程序。目标 1 利用 具有 SMC 特异性删除 Smad3 和并发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 细胞命运和由此产生的疾病解剖学的影响。然后我们将申请 对病变细胞进行单细胞转录分析，以检查不同 SMC 中的转录程序 后代，并结合这些数据集来了解 CAD 风险如何由 Smad3 特别是在 SMC 中介导 在细胞水平上。目标2应用人冠状动脉平滑肌细胞模型来研究 SMAD3 通过全基因组识别增强子来调节转录程序 SMAD3 及其转录调控作用。我们还将这一发现与另一个数据重叠 平滑肌表达的 CAD 风险相关转录因子 TCF21，以进一步了解 调节 CAD 风险的 SMC 转录程序。总之，这些研究将显着扩展我们的 了解 SMC 表达的转录因子 SMAD3 和 TCF21 在 CAD 中的作用，以及 显着增进我们对因果变异介导 CAD 风险机制的理解 希望在未来产生新的治疗策略。