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: 7570104
• 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/7570104
• 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; Contractile Proteins; Coronary Artery Bypass; Cytoskeletal Proteins; Data; Development; Disease; Disease model; Electrophoretic Mobility Shift Assay; Elements; 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; 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; neointima formation; novel; overexpression; 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）通常表现出分化的收缩表型。它们的主要功能包括通过收缩状态调节血管张力，并合成作为血管的结构成分的细胞外基质支架。为了应对动脉损伤或高胆固醇血症，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变窄，从而经历表型变化。这种表型变化和随后的血管阻塞会引起组织缺血或导致心肌梗塞。关于控制这些过程的蛋白质作用的知识存在明显的差距。我们的长期目标是了解基因的转录控制，这些基因受到新的vSMC的调节，以及它们编码的蛋白质有助于血管疾病进展的机制。我们的研究已经确定了一种分泌的蛋白质，主动脉羧肽酶样蛋白（ACLP），该蛋白（ACLP）在NeImnimal VSMC中诱导。 ACLP转录不是由CARG Box-Serum响应因子（SRF）相互作用介导的，表明对ACLP调控的研究可能阐明了血管疾病中VSMC基因调节的新方面。我们已经产生了ACLP-NULL小鼠，我们的初步结果表明，股动脉损伤响应这些小鼠的新内膜较小，增殖性VSMC较少，并且从这些ACLP-NULL小鼠中分离出的VSMC表现出降低的增殖能力。与ACLP在VSMC增殖中的作用一致，ACLP的腺病毒过表达刺激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内膜形成的重要调节剂。我们的目标是研究ACLP在股动脉损伤模型中使用ACLP-NULL小鼠在新内膜形成进展中的作用；研究ACLP促进VSMC增殖的机制，通过研究培养中的VSMC来表征ACLP-纤维细胞基质和生长因子相互作用。并研究体外ACLP表达的SRF无关调节，并确定使用转基因小鼠和血管疾病模型在Neidimal vSMC中ACLP表达所需的启动子元素。提出的实验将提供有关调节VSMC增殖的分子机制的重要新知识。这些对ACLP转录控制和VSMC中功能的研究可能会导致用于动脉粥样硬化的新治疗方法，并预防冠状动脉搭桥或血管成形术后再狭窄。