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：
8726461
负责人：
DIANNA M MILEWICZ
金额：
$ 203.52万
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/8726461
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 rare variant 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在多层的动脉中周围排列，要么在大型弹性动脉中嵌入弹性蛋白薄片层之间，要么在较小的肌肉动脉中的连接组织的基质中嵌入。对于收缩功能，SMCs表达α-肌动蛋白和β-肌球蛋白的平滑肌特异性同工型，它们分别多种形式形成形成薄细丝。我们已经确定，编码SMCα-肌动蛋白和β-肌动蛋白，ACTA2和MYH11的基因突变以及控制SMC收缩，肌球蛋白光链激酶（MYLK）的激酶，易感性个体，包括血管疾病，包括早期的胸腔疾病和肌肉疾病，诸如胸腔疾病和倾向性疾病，诸如肌肉疾病，诸如鼻腔疾病，既有症状疾病疾病综合性疾病，均为脑部疾病。疾病和中风。计划项目赠款（PPG）将检验以下假设：ACTA2，MYH11和MYLK突变导致胸腔主动脉疾病和疾病和/或闭塞性血管疾病，这是由于SMC对生物力学应力的不同反应引起的生物力学应激，导致收缩单位功能障碍。我们假设这些基因中的突变会导致功能丧失，特别是调节的损失或升主动脉中SMC中收缩单位的力输出变化，从而导致生物力学应力增加以及SMC途径的激活导致胸动脉主动脉瘤和主动脉瘤。 In contrast, we hypothesize that the occlusive vascular diseases associated with a subset of ACTA2 mutations, and possible 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.检验这些假设。项目1和2将评估ACTA2和MYH11遗传变异对动力学，运动，调节和细丝形成的影响。项目3将评估在特定信号传导模块中依赖年龄的演变，这些模块是在选择ACTA2，MYH11和MYLK突变的小鼠模型中血管舒缩反应性的。项目4将研究这些小鼠模型中导致胸腔主动脉疾病和SMC增殖的SMC细胞途径。