The regulatory roles of nuclear SM22 in smooth muscle phenotypic modulation

核SM22在平滑肌表型调节中的调节作用

• 批准号: 9978091
• 负责人: LI LI
• 金额: $ 52.22万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978091
• 关键词: Actin-Binding Protein; Actins; Acute; Address; Arteries; Binding; Bioinformatics; Blood Vessels; Cell Differentiation process; Cell Nucleus; Cell physiology; Chronic; Clinical; Competitive Binding; Cytoskeleton; Development; Disease; Down-Regulation; Drug Targeting; Epigenetic Process; Family; Feedback; Fibrosis; Future; Genes; Genetic; Genetic Transcription; Goals; In Vitro; Inflammation; Injury; Intervention; Knockout Mice; Knowledge; Lead; Mediating; Methods; Mission; Molecular; NF-kappa B; Nuclear; Nuclear Translocation; Pathogenesis; Pathogenicity; Pathologic; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Play; Process; Protein Deficiency; Proteins; Public Health; Publishing; Research; Role; Serum Response Factor; Smooth Muscle; Smooth Muscle Myocytes; Systems Biology; Testing; Therapeutic; Transgenic Mice; United States National Institutes of Health; Vascular Diseases; Vascular Smooth Muscle; Work; base; calponin; cell dedifferentiation; cofactor; dosage; improved; injured; innovation; member; myocardin; prevent; response; transcription factor; transcriptome; vascular injury

Project Summary: Vascular smooth muscle cell (SMC) phenotypic modulation plays critical roles in the pathogenesis of vascular diseases. SRF (Serum Response Factor) is a critical transcription factor that plays a central role in regulating gene transcription in SMC phenotypic modulation by competitively binding with Myocardin (the key differentiation regulator) and other key transcription regulators such as Elk and NF-kB. Extensive studies have characterized the mechanisms of actin-Myocardin interaction in SRF-mediated transcription, yet surprisingly the question of whether actin directly targets SRF to modulate SMC differentiation and phenotypic modulation has not been addressed. Downregulation of actin cytoskeleton proteins including actin and SM22 (an actin binding protein) has long been recognized as a marker of SMC phenotypic modulation and was until now regarded as a consequence of SMC dedifferentiation. However, we have now accumulated compelling evidence suggesting that SM22 but not actin can target SRF to regulate its transcriptional activities. The goal of this project is to characterize the molecular mechanisms of SM22 in coordinatively regulating the transcription of a variety of genes involved in SMC modulation from contractile phenotype to pathogenic phenotypes. Based on our published work and exciting preliminary results, we hypothesize that SM22 regulates SMC phenotypes as a transcription cofactor to modulate the interplay of SRF and other key transcription regulators for SMC differentiation and dedifferentiation in the vessel wall. We will take the system biology approach using integrated molecular, cellular, genetic, and bioinformatics methods to test this hypothesis. The Specific Aims are (i) to determine the molecular mechanisms whereby SM22 regulates the function of SRF in SMC phenotypic modulation in cultured SMCs. (ii) to determine the roles of SM22 in the pathogenesis of vascular wall remodeling in response to vascular injury using knockout and transgenic mice generated in our lab. Successful completion of this project will likely validate a new paradigm whereby actin cytoskeleton proteins actively participate in regulating smooth muscle phenotypic modulation during the pathogenesis of vascular diseases. We expect that the proposed studies will have the positive impact of identifying cytoskeleton proteins as a new class of targets for future pharmaceutical intervention.

项目摘要：血管平滑肌细胞(SMC)的表型调节在动脉粥样硬化中起关键作用。 血管疾病的发病机制。SRF(血清反应因子)是一种关键的转录因子，它发挥着 竞争结合在SMC表型调控基因转录中的中心作用 Myocardin(关键的分化调节因子)和其他关键的转录调节因子，如ELK和NF-kB。 广泛的研究已经表征了肌动蛋白-肌钙蛋白在SRF介导下的相互作用机制 转录，但令人惊讶的是，肌动蛋白是否直接针对SRF来调节SMC分化 而表型调控尚未得到解决。肌动蛋白细胞骨架蛋白的下调包括 肌动蛋白和SM22(一种肌动蛋白结合蛋白)长期以来一直被认为是SMC表型的标志 到目前为止，它被认为是SMC去分化的结果。然而，我们现在有 累积的令人信服的证据表明，SM22而不是肌动蛋白可以靶向SRF来调节其 转录活动。本项目的目标是研究SM22的分子机制。 协同调控多种参与SMC收缩调控的基因转录 从表型到致病表型。基于我们已发表的工作和令人振奋的初步结果，我们 假设SM22作为转录辅因子调节SMC表型以调节SRF的相互作用 以及管壁中SMC分化和去分化的其他关键转录调节因子。我们会 采用系统生物学方法，使用集成的分子、细胞、遗传和生物信息学方法 检验这一假设。其具体目的是：(1)确定SM22 调节SRF在培养的SMC表型调节中的作用。(Ii)确定以下人员的角色 SM22在血管损伤后血管壁重塑发病机制中的作用 本实验室培育的转基因小鼠。这个项目的成功完成很可能会验证一种新的范式 肌动蛋白细胞骨架蛋白积极参与调节平滑肌表型改变 在血管疾病的发病机制中。我们期望拟议的研究将产生积极的影响 将细胞骨架蛋白确定为未来药物干预的新靶点的影响。