Chromatin Remodeling in Smooth Muscle Myogenesis and Vascular Injury Responses

平滑肌肌生成和血管损伤反应中的染色质重塑

• 批准号: 7463613
• 负责人: LI LI
• 金额: $ 37.63万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-06 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463613
• 关键词: Affect; Arteries; Binding; Biochemical; Biochemical Genetics; Bioinformatics; Biological Assay; Blood Vessels; Boxing; COS Cells; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Chromatin; Class; Complex; Core Facility; Coronary artery; Deacetylase; Deacetylation; Developmental Biology; Embryo; Epigenetic Process; Equilibrium; Family; Fibroblasts; Genetic Transcription; Goals; Heart Hypertrophy; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histones; Human; In Vitro; Injury; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Medial; Mediating; Methylation; Michigan; Modification; Molecular; Mus; Mutation; Myofibroblast; Pathogenesis; Pattern; Physical condensation; Play; Protein Overexpression; Recruitment Activity; Research Personnel; Role; Services; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Sodium Butyrate; TGFB1 gene; Testing; Transcription Coactivator; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Trichostatin A; Universities; Vascular Diseases; atherogenesis; cell growth; chromatin remodeling; histone acetyltransferase; in vivo; inhibitor/antagonist; injured; innovation; member; mouse model; mutant; myocardin; myogenesis; novel; promoter; response; response to injury; restenosis; stable cell line; tool

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular mechanisms that regulate smooth muscle cell (SMC) phenotypic changes during smooth muscle myogenesis and in the pathogenesis of human vascular diseases. Recent extensive biochemical and genetic studies have provided substantial evidence showing that the balance of histone acetylation and deacetylation is crucial to the control of cell proliferation in cancer and cardiac hypertrophy. However, little is known about how manipulating histone acetylation controls SMC gene transcription and proliferation in human vascular diseases. The goal of this application is to determine the molecular mechanisms whereby histone modifiers, especially HDAC8, regulate SMC gene transcription both in vitro and in vivo. This study integrates innovative transgenic/knockout mice, BAG recombineering and bioinformatics tools into classic biochemical, molecular and developmental biology approaches. The results of this study will not only fill a gap in our understanding of HDACs in transcriptional regulation, but also further our knowledge of epigenetic mechanisms in regulating SMC myogenesis^ Extensive studies demonstrate that the dynamic changes of histone acetylation and deacetylation play important roles in gene transcription and cell proliferation. HDACS is a member of the class I HDAC (histone deacetylase) family, and possesses histone deacetylase activities. Our preliminary results show that HDACS, unlike other HDACs, acts as a transcriptional activator for SMC gene transcription. We hypothesize that HDACS is a pro-SMC differentiation factor that modulates SRF/Myocardin and SmadS-mediated SMC transcriptional regulatory complexes. The specific aims are: (1) to determine whether HDACS affects histone modification at the SM22 locus in vitro, and whether the deacetylase activity of HDACS is required to enhance the pro-myogenic activities of SMC regulators; (2) to determine how HDACS interacts with the SMC transcriptional regulatory network and TGFpl signal pathway; (3) to determine whether histone deacetylase inhibitors affect atherogenesis and how HDACS modulates SMC differentiation in SMC myogenesis and in injury-induced restenosis in vivo. Given the important roles of histone modification in SMC growth and differentiation, the results of this study will contribute significantly towards developing novel therapeutical strategies targeted at the epigenetic mechanisms affecting the abnormal SMC-associated human vascular diseases.

描述（由申请人提供）：该项目的长期目标是了解平滑肌肌生成过程中以及人类血管疾病发病机制中调节平滑肌细胞（SMC）表型变化的分子机制。最近广泛的生化和遗传学研究提供了大量证据，表明组蛋白乙酰化和脱乙酰化的平衡对于控制癌症和心脏肥大中的细胞增殖至关重要。然而，关于在人类血管疾病中如何操纵组蛋白乙酰化来控制 SMC 基因转录和增殖，人们知之甚少。本申请的目标是确定组蛋白修饰剂（尤其是 HDAC8）在体外和体内调节 SMC 基因转录的分子机制。这项研究将创新的转基因/基因敲除小鼠、BAG 重组工程和生物信息学工具整合到经典的生化、分子和发育生物学方法中。这项研究的结果不仅将填补我们对HDACs转录调控的认识空白，还将进一步加深我们对调节SMC肌生成的表观遗传机制的认识^大量研究表明组蛋白乙酰化和脱乙酰化的动态变化在基因转录和细胞增殖中发挥着重要作用。 HDACS 是 I 类 HDAC（组蛋白脱乙酰酶）家族的成员，具有组蛋白脱乙酰酶活性。我们的初步结果表明，与其他 HDAC 不同，HDACS 充当 SMC 基因转录的转录激活子。我们假设 HDACS 是一种前 SMC 分化因子，可调节 SRF/Myocardin 和 SmadS 介导的 SMC 转录调节复合物。具体目的是：（1）确定HDACS在体外是否影响SM22位点的组蛋白修饰，以及HDACS的脱乙酰酶活性是否需要增强SMC调节剂的促肌生成活性； (2)确定HDACS如何与SMC转录调控网络和TGFpl信号通路相互作用； (3) 确定组蛋白脱乙酰酶抑制剂是否影响动脉粥样硬化形成以及 HDACS 如何在 SMC 肌生成和损伤诱导的体内再狭窄中调节 SMC 分化。鉴于组蛋白修饰在 SMC 生长和分化中的重要作用，这项研究的结果将显着有助于开发针对影响异常 SMC 相关人类血管疾病的表观遗传机制的新型治疗策略。