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: 9766379
• 负责人: LI LI
• 金额: $ 51.45万
• 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/9766379
• 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

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）表型调节在 血管疾病的发病机理。 SRF（血清反应因子）是扮演的关键转录因子 通过与与SMC表型调节中基因转录的中心作用，通过与 心肌（关键分化调节剂）和其他关键转录调节剂，例如ELK和NF-KB。 广泛的研究表征了SRF介导的肌动蛋白 - 肌动蛋白相互作用的机制 转录，但令人惊讶的是，肌动蛋白是否直接靶向SRF来调节SMC分化的问题 尚未解决表型调制。肌动蛋白细胞骨架蛋白的下调包括 肌动蛋白和SM22（肌动蛋白结合蛋白）长期以来一直被认为是SMC表型的标记 调制，直到现在被视为SMC去分化的结果。但是，我们现在有 积累了令人信服的证据，表明SM22而不是肌动蛋白可以针对SRF来调节其 转录活动。该项目的目的是表征SM22的分子机制 协调调节收缩涉及SMC调制的各种基因的转录 致病表型的表型。根据我们发表的工作和令人兴奋的初步结果，我们 假设SM22调节SMC表型作为转录辅因子来调节SRF的相互作用 以及其他用于SMC分化和排化的关键转录调节剂。我们将 使用集成的分子，细胞，遗传和生物信息学方法采用系统生物学方法 检验此假设。具体目的是（i）确定SM22的分子机制 调节SRF在SMC表型调制中的功能。 （ii）确定 SM22在血管壁重塑的发病机理中，响应使用敲除和 在我们的实验室中产生的转基因小鼠。该项目的成功完成可能会验证新的范式 肌动蛋白细胞骨架蛋白积极参与调节平滑肌表型调节 在血管疾病的发病机理中。我们希望拟议的研究将具有积极的 将细胞骨架蛋白识别为未来药物干预的新目标的影响。