Role of ACLP in Vascular Smooth Muscle Biology

ACLP 在血管平滑肌生物学中的作用

• 批准号: 7345391
• 负责人: MATTHEW D LAYNE
• 金额: $ 40.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345391
• 关键词: Angioplasty; Animals; Arterial Fatty Streak; Atherosclerosis; Binding; Biology; Blood Vessels; Boxing; Bromodeoxyuridine; Carboxypeptidase; Cell Count; Cell Differentiation process; Cellular biology; Collagen; Complex; Condition; Contractile Proteins; Coronary Artery Bypass; Cytoskeletal Proteins; Data; Development; Disease; Disease model; Electrophoretic Mobility Shift Assay; Elements; Epithelial Discoidin Domain Receptor 1; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillar Collagen; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth Factor Interaction; In Vitro; Injury; Ischemia; Knockout Mice; Knowledge; LacZ Genes; Lead; Mediating; Modeling; Molecular; Mus; Myocardial Infarction; Myosin Heavy Chains; Pattern; Phenotype; Platelet-Derived Growth Factor; Prevention; Process; Proliferating; Protein Overexpression; Proteins; Publishing; Regulation; Regulatory Element; Reporter; Research Personnel; Role; Serum Response Factor; Signal Transduction; Smooth Muscle Myocytes; Smooth Muscle Myosins; Tissues; Transcriptional Regulation; Transfection; Transgenic Mice; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; calponin; discoidin receptor; femoral artery; gain of function; hypercholesterolemia; in vivo; insight; mouse Smc1l1 protein; mouse Smc1l2 protein; neointima formation; novel; platelet-derived growth factor BB; programs; promoter; protein expression; research study; response; response to injury; restenosis; scaffold; transcription factor; transgene expression; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Vascular smooth muscle cells (VSMC) in the blood vessel wall normally exhibit a differentiated, contractile phenotype. Their primary functions include modulating vascular tone through their contractile state and synthesizing the extracellular matrix scaffold that serves as a structural component of the blood vessel. In response to arterial damage or hypercholesterolemia, VSMC undergo a phenotypic change by down- regulating contractile protein expression, proliferate, and migrate leading to neointima formation and blood vessel narrowing. This phenotypic change and subsequent vessel occlusion can cause tissue ischemia or lead to myocardial infarction. There is a clear gap in knowledge concerning the role of proteins that control these processes. Our long-term goals are to understand the transcriptional control of genes, which are up- regulated in neointimal VSMC, and the mechanisms by which their encoded proteins contribute to the progression of vascular disease. Our studies have identified a secreted protein, aortic carboxypeptidase-like protein (ACLP) that is induced in neointimal VSMC. ACLP transcription is not mediated by CArG box-serum response factor (SRF) interactions indicating that the study of ACLP regulation may elucidate novel aspects of VSMC gene regulation in vascular disease. We have generated ACLP-null mice and our preliminary results indicate that in response to femoral artery injury these mice have a smaller neointima with fewer proliferative VSMC, and VSMC isolated from these ACLP-null mice exhibit a reduced proliferative capacity. Consistent with a role for ACLP in VSMC proliferation, adenoviral overexpression of ACLP stimulates PDGF- mediated VSMC proliferation. Our central hypothesis is that ACLP is an important regulator of blood vessel neointima formation under pathological conditions. Our goals are to investigate the role of ACLP in the progression of neointima formation using ACLP-null mice in a femoral artery injury model; investigate the mechanisms by which ACLP promotes VSMC proliferation, characterize ACLP-extracellular matrix and growth factor interactions by studying VSMC in culture; and to investigate the SRF-independent regulation of ACLP expression in vitro and determine the promoter elements required for ACLP expression in neointimal VSMC in vivo using transgenic mice and vascular disease models. The proposed experiments will provide important new knowledge about the molecular mechanisms regulating VSMC proliferation. These studies on ACLP transcriptional control and function in VSMC may lead to novel treatment approaches for atherosclerosis and the prevention of restenosis after coronary bypass or angioplasty.

描述（由申请人提供）：血管壁中的血管平滑肌细胞（VSMC）通常表现为分化的、收缩的表型。它们的主要功能包括通过收缩状态调节血管张力和合成作为血管结构成分的细胞外基质支架。在动脉损伤或高胆固醇血症的反应中，VSMC通过下调收缩蛋白表达、增殖和迁移导致新内膜形成和血管狭窄而发生表型改变。这种表型改变和随后的血管闭塞可引起组织缺血或导致心肌梗死。关于控制这些过程的蛋白质的作用，在知识方面存在明显的空白。我们的长期目标是了解新内膜VSMC中上调的基因的转录控制，以及它们编码的蛋白质促进血管疾病进展的机制。我们的研究已经确定了一种分泌蛋白，主动脉羧基肽酶样蛋白（ACLP），可诱导新生内膜VSMC。ACLP转录不受CArG盒-血清反应因子（SRF）相互作用的介导，这表明ACLP调控的研究可能阐明血管疾病中VSMC基因调控的新方面。我们培育了aclp缺失的小鼠，我们的初步结果表明，在对股动脉损伤的反应中，这些小鼠的新内膜更小，增殖性VSMC更少，从这些aclp缺失的小鼠中分离的VSMC表现出较低的增殖能力。与ACLP在VSMC增殖中的作用一致，腺病毒过表达ACLP刺激PDGF介导的VSMC增殖。我们的中心假设是ACLP是病理条件下血管新生内膜形成的重要调节因子。我们的目的是研究ACLP在股动脉损伤模型中ACLP缺失小鼠新生内膜形成过程中的作用；通过培养VSMC研究ACLP促进VSMC增殖的机制，表征ACLP与细胞外基质及生长因子的相互作用；并利用转基因小鼠和血管疾病模型研究体外ACLP表达的srf独立调控，确定体内新生内膜VSMC中ACLP表达所需的启动子元件。本实验将为研究VSMC增殖的分子机制提供重要的新知识。这些关于ACLP在VSMC中的转录控制和功能的研究可能会为动脉粥样硬化和冠状动脉搭桥或血管成形术后再狭窄的预防提供新的治疗方法。