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ACTA2, MYH11, and MYLK Mutations Affecting Smooth Muscle Contraction

ACTA2、MYH11 和 MYLK 突变影响平滑肌收缩

基本信息

批准号：
9123665
负责人：
JAMES T STULL
金额：
$ 55.7万
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：
资助国家：
美国
起止时间：
至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123665
关键词：
Actins Adhesions Affect Agonist Alleles Aorta Aortic Segment Arteries Attenuated Binding Proteins Biochemical Biological Blood Vessels Cell Adhesion Cell Proliferation Cell-Matrix Junction Cells Clinical Collagen Contractile Proteins Defect Dermal Development Disease Dissection F-Actin Fibroblasts Filament Focal Adhesions Functional disorder G Actin Health Human Hypertension In Vitro Instruction Knock-in Knock-out Lead Light Link MYH11 gene MYLK gene Measurement Mechanical Stress Mesenteric Arteries Microfilaments Molecular Molecular Motors Mus Muscle Muscle Contraction Mutate Mutation Myofibroblast Myosin ATPase Myosin Heavy Chains Myosin Light Chain Kinase Myosin Regulatory Light Chains Output Pathology Pathway interactions Patients Performance Phenotype Phosphorylation Process Property Protein Isoforms Proteins Research Research Project Grants Resistance Signal Transduction Signaling Protein Smooth Muscle Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Testing Thoracic Aortic Aneurysm Tissues Vascular Diseases Vascular Smooth Muscle Vascular Smooth Muscle Tissue Vasomotor age related ascending aorta base disease-causing mutation factor A insight mutant myocardin novel novel strategies paxillin polymerization protein expression response transcription factor

项目摘要

Familial thoracic aortic aneurysms and dissection (TAAD) are linked to mutations in smooth muscle myosin heavy chain, actin and myosin light chain kinase (MLCK. We will test the overarching hypothesis that disease-causing mutations reduce smooth muscle contractile function. Aim 1: Test the hypothesis that MYH11 mutations that cause TAAD impair contractile output of smooth muscle cells. We will analyze aortic smooth muscle tissues from genetically modified mice for age-dependent adaptive changes in (1) expression of proteins in distinct adhiesion and contractile signaling modules, (2) [Ca2+]i and vasomotor performance in tissue rings in response to agonists, and (3) phosphorylation that activates the contractile myosin (RLC) or focal adhesion (paxillin) signaling modules. Aim 2: Test the hypothesis that heterozygous loss of MLCK activity impairs contractile output because of attenuated RLC phosphorylation in smooth muscle cells and leads to development of TAAD in the ascending aorta. Aim 3: Test the hypothesis that ACTA2 mutations that cause TAAD impair contractile output of smooth muscles. We will analyze the adhesion and contractile signaling modules as described in Aim 1 to determine if specific actin mutations promote selective dysfunction in one module or both. Aim 4: Test the hypothesis that ACTA2 mutations perturb myofibroblast contractions. MRTF-A will be used to induce myofibroblast phenotype expressing high amounts of smooth muscle a-actin in human dermal fibroblasts from patients harboring mutations in ACTA2. These studies will provide insights into the cellular basis of contractile performance defects associated with ACTA2 and MYH11 mutations examined at a molecular level in research Projects 1 and 2, and cellular pathways associated with reorganization of focal adhesions in mutant cells (Project 4). We also will continue collaborative studies on MLCK with Project 4.The synergy of our research interactions will provide an understanding of the molecular mechanisms that influence vascular disease based on the hypothesis that ACTA2, MYH11 and MYLK mutations lead to TAAD and occlusive vascular diseases due to selective dysfunctions of the contractile process. RELEVANCE (See instructions): We plan to establish the quantitative importance specific proteins responsible for the contractile responses of smooth muscle cells in blood vessels in health which may be deranged with mutations associated with TAAD. Characterization of key signaling proteins will provide perspectives on clinical strategies for novel pharmacological targets to manage TAAD, and potentially on cellular adaptations that may contribute to derangement of contractile responses involving smooth muscle in other vascular diseases.

家族性胸主动脉瘤和夹层（TAAD）与平滑肌突变有关