Control of Smooth Muscle Cell (SMC) Differentiation and Phenotype Switching

平滑肌细胞 (SMC) 分化和表型转换的控制

• 批准号: 7746393
• 负责人: Gary K Owens
• 金额: $ 59.6万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7746393
• 关键词: Actins; Adult; Agonist; Angioplasty; Angiotensin II; Apolipoprotein E; Atherosclerosis; Binding; Blood Vessels; Cardiovascular Diseases; Cell Culture System; Cell Differentiation process; Cell Lineage; Cell Maturation; Cells; Chromatin Structure; Collaborations; Consensus; Coronary artery; Cues; Development; Differentiation Antigens; Differentiation and Growth; Disease; Elements; Enhancers; Family; Figs - dietary; Gene Activation; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Histones; Injury; Investigation; Knock-out; Matrix Metalloproteinases; Mediating; Modification; Molecular; Organ; Pathogenesis; Pattern; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Play; Process; Receptor Signaling; Regulation; Regulatory Element; Rho-associated kinase; Role; Signal Pathway; Smooth Muscle Myocytes; Testing; Transgenic Mice; Vascular Diseases; atherogenesis; chromatin modification; embryonic stem cell; gene repression; human disease; in vivo; insight; member; myocardin; programs; promoter; receptor; response; restenosis; rho; smoothened signaling pathway; transcription factor

Alterations in the differentiated state of the smooth muscle cell (SMC) play a key role in the development and/or progression of a variety of cardiovascular diseases. The tong-term goal of this project has been to elucidate cellular and molecular mechanisms that control the growth and differentiation of SMC during vascular development, and to determine how these control processes are altered during phenotypic switching of SMC in association with vascular injury and disease. A key to understanding these processes is to identify environmental cues (or factors) that influence the differentiated state of SMC and to determine mechanisms and signaling pathways whereby these factors alter expression of genes required for the differentiated function of the SMC. The focus of studies in this proposal is to test the hypothesis that the SMC selective SRF co-activator myocardin or myocardin- like factors function as a point of convergence for regulation of SMC gene expression in response to both positive and negative regulators of SMC differentiation such as angiotensin II (A-II) and PDGF BB respectively and that these factors exert their effects at least in part by histone dependent modifications in chromatin structure that influence binding of SRF-myocardin to CArG elements within SMC promoter-enhancers. Aim 1 will determine the role and mechanisms by which PDGF BB regulates differentiation of vascular SMC and will include determining the role of KLF4, Sp1/3, and chromatin modifications in PDGF BB induced suppression of SMC marker genes (Aim 1a), as well as determining effects of SMC targeted knockout of the PDGF beta-receptor or KLF4 on SMC maturation during development, and phenotypic switching following vascular injury or ApoE -/- experimental atherogenesis in vivo (Aim 1b). Aim 2 will determine the molecular mechanisms whereby A-II and other contractile agonists promote expression of SMC marker genes including testing the hypothesis that effects are mediated in part through increased expression and/or recruitment of myocardin-SRF (or MAL-SRF) to degenerate CArG elements contained within the promoters of virtually all SMC marker genes, as well as through rho kinase dependent mechanisms. The proposed studies involve extensive interactions with each Project within this Program Project. Taken together, studies will provide key insights regarding cellular/molecular mechanisms that control differentiation of SMC, and contribute to understanding the role these processes might play in development of cardiovascular disease.

平滑肌细胞（SMC）分化状态的改变在多种心血管疾病的发展和/或进展中起关键作用。该项目的倾斜度目标是阐明控制血管发育过程中SMC生长和分化的细胞和分子机制，并确定在SMC与血管损伤和疾病相关的表型转换过程中如何改变这些控制过程。理解这些过程的关键是确定影响SMC差异化状态的环境线索（或因素），并确定机制和机制和机制和 这些因素改变了SMC分化功能所需的基因表达的信号通路。 The focus of studies in this proposal is to test the hypothesis that the SMC selective SRF co-activator myocardin or myocardin- like factors function as a point of convergence for regulation of SMC gene expression in response to both positive and negative regulators of SMC differentiation such as angiotensin II (A-II) and PDGF BB respectively and that these factors exert their effects at least in part by histone dependent modifications in影响SRF-肌动蛋白与SMC内CARG元素结合的染色质结构 发起人增强剂。 AIM 1将确定PDGF BB调节血管SMC的差异的作用和机制，并包括确定KLF4，SP1/3的作用，以及在PDGF BB诱导SMC标记基因抑制SMC基因（AIM 1A）中的染色质修饰（AIM 1A）（AIM 1A）（AIM 1A）的作用（AIM 1A），以及在SMC靶标在SMC of smc ofs of smc ofs of smc nockOut ot smc of pdgf beta的效果中的影响。血管损伤或APOE - / - 体内实验性动脉粥样硬化后的表型切换（AIM 1B）。 AIM 2将确定A-II和其他收缩激动剂的分子机制促进SMC标记基因的表达，包括检验假设，即通过增加表达和/或肌电蛋白-SRF（或MAL-SRF）对内部包含的变性CARG元素的表达和/或募集来部分介导的假设。 几乎所有SMC标记基因的启动子以及通过Rho激酶依赖机制的启动子。拟议的研究涉及与该计划项目中每个项目的广泛互动。综上所述，研究将提供有关控制SMC分化的细胞/分子机制的关键见解，并有助于理解这些过程在心血管疾病发展中的作用。