Mutations in Smooth Muscle Contractile Proteins: Pathways to Vascular Diseases

平滑肌收缩蛋白突变：血管疾病的途径

基本信息

批准号：
8536675
负责人：
DIANNA M MILEWICZ
金额：
$ 197.24万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-25 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536675
关键词：
Actins Actomyosin Address Adhesions Affect Age Agonist Alleles Amino Acids Aneurysm Aortic Aneurysm Aortic Diseases Arteries Attenuated Automobile Driving Benign Binding Biological Biological Assay Biomechanics Blood Vessels Budgets Cancer Etiology Carotid Artery Injuries Cell physiology Cells Cellular Assay Chest Clinical Collaborations Colon Carcinoma Connective Tissue Contractile Proteins Coronary Arteriosclerosis DNA Sequence Rearrangement Data Defect Dermal Development Diagnostic Diagnostic tests Dilatation - action Disease Disease Progression Dissection Doctor of Medicine Doctor of Philosophy Drug Formulations Elastin Electron Microscopy Evolution F-Actin Fibroblasts Filament Focal Adhesion Kinase 1 Focal Adhesions Functional disorder Generations Genes Genetic Polymorphism Genetic Research Genotype Goals Health Sciences Homo Human Image Imatinib Impairment In Vitro Individual Inherited Investigation Kinetics Knock-out Laboratories Lasers Lead Length Lesion Link MYH11 gene MYLK gene Medical center Microfilaments Missense Mutation Mitochondria Molecular Motion Mus Muscle Muscle Contraction Mutant Strains Mice Mutation Myofibroblast Myosin ATPase Myosin Light Chain Kinase Output Oxidative Stress PDGFRB gene Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Penetrance Pennsylvania Performance Phenotype Phosphorylation Phosphotransferases Platelet-Derived Growth Factor beta Receptor Point Mutation Process Production Program Research Project Grants Property Protein Isoforms Proteins Reactive Oxygen Species Recruitment Activity Regulation Research Research Personnel Research Project Grants Risk Role Signal Pathway Signal Transduction Slide Smooth Muscle Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Smooth Muscle Myosins Staining method Stains Stress Stroke Structure System Technical Expertise Testing Texas Thick Filament Thin Filament Thoracic Aortic Aneurysm Time Tissues Transgenic Mice Tropomyosin Tyrosine Kinase Inhibitor Universities Variant Vascular Diseases Vasomotor Vermont Work actin 2 age related alpha Actin ascending aorta assay development base beta-Myosin cell motility clinical risk design early onset frontier gain of function genetic variant high risk in vitro Assay in vivo inhibitor/antagonist insight loss of function molecular imaging monomer mouse model mutant novel paxillin polymerization prevent programs protein expression protein function receptor response response to injury single molecule therapeutic target

项目摘要

Vascular SMCs are arranged circumferentially in arteries in multiple layers, either embedded between layers of elastin lamellae in large elastic arteries or in a matrix of connective tissue in smaller muscular arteries. For contractile function, SMCs express smooth muscle specific isoforms of alpha-actin and Beta-myosin, which multimerize to form thin and thick filaments, respectively. We have determined that mutations in the genes encoding SMC alpha-actin and Beta-myosin, ACTA2 and MYH11, along with the kinase that controls SMC contraction, myosin light chain kinase (MYLK), predispose individuals to vascular diseases, including thoracic aortic aneurysms and aortic dissections and occlusive vascular diseases, such as early onset coronary artery disease and stroke. The Program Project Grant (PPG) will test the hypothesis that the ACTA2, MYH11 and MYLK mutations lead to thoracic aortic and disease and/or occlusive vascular diseases due to a differential SMC response to biomechanical stresses resulting from dysfunction of the contractile unit. We hypothesize that mutations in these genes cause a ¿loss of function¿, specifically loss of regulation or altered force output of contractile unit in SMCs in ascending aorta, resulting in increased biomechanical stresses and activation of SMC pathways leading to thoracic aortic aneurysms and aortic dissections. In contrast, we hypothesize that the occlusive vascular diseases associated with a subset of ACTA2 mutations, and possibly MYH11 variants, result from a SMC "gain of function" in muscular arteries, specifically increased SMC proliferation as a consequence of altered focal adhesions and activation of PDGFR-Beta receptors in response to abnormal cellular force generation. To test these hypotheses. Project 1 and 2 will assess the Impact of ACTA2 and MYH11 genetic variants on kinetics, motility, regulation, and filament formation in vitro. Project 3 will assess age-dependent derangements in specific signaling modules responsible for vasomotor responsiveness in vascular SMCs in mouse models of select ACTA2, MYH11 and MYLK mutations. Project 4 will Investigate SMC cellular pathways leading to thoracic aortic disease and SMC proliferation in these same mouse models.

血管 SMC 在动脉中呈多层排列，要么嵌入大弹性动脉的弹性蛋白层之间，要么嵌入较小肌性动脉的结缔组织基质中。为了实现收缩功能，SMC 表达平滑肌特异性的 α-肌动蛋白和 β 亚型。 -肌球蛋白，它们分别多聚形成细丝和粗丝，我们已经确定编码 SMC α-肌动蛋白和 β-肌球蛋白的基因发生突变。 ACTA2 和 MYH11 以及控制 SMC 收缩的激酶、肌球蛋白轻链激酶 (MYLK) 使个体易患血管疾病，包括胸主动脉瘤和主动脉夹层以及闭塞性血管疾病，例如早发性冠状动脉疾病和中风。资助计划 (PPG) 将检验 ACTA2、MYH11 和 MYLK 突变导致胸主动脉疾病的假设和/或由于收缩单位功能障碍导致的 SMC 对生物力学应激的不同反应而导致的闭塞性血管疾病。功能丧失¿ ，特别是升主动脉 SMC 收缩单位的调节丧失或力量输出改变，导致生物力学应力增加和 SMC 通路激活，导致胸主动脉瘤和主动脉夹层。相反，我们抵制与闭塞性血管疾病相关的疾病。 ACTA2 突变的子集，以及可能的 MYH11 变异，是由肌动脉中 SMC“获得功能”引起的，特别是因此增加了 SMC 增殖为了测试这些假设，项目 1 和 2 将评估 ACTA2 和 MYH11 遗传变异对体外动力学、运动性、调节和细丝形成的影响。项目 3 将评估特定信号模块中与年龄相关的紊乱，这些信号模块负责选定 ACTA2、MYH11 和MYLK 突变。项目 4 将在这些相同的小鼠模型中研究导致胸主动脉疾病和 SMC 增殖的 SMC 细胞途径。