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Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization

α-连环蛋白在心肌细胞粘附和细胞骨架组织中的功能

基本信息

批准号：
9104366
负责人：
Adam Vincent Kwiatkowski
金额：
$ 37.77万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104366
关键词：
Actin-Binding Protein Actins Actomyosin Adherens Junction Adhesions Adhesives Affect Binding Binding Sites Biology Cadherins Cardiac Cardiac Myocytes Cardiomyopathies Cell membrane Cell-Cell Adhesion Cells Cellular biology Chemicals Communication Complex Contracts Couples Coupling Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Data Desmosomes Development Epithelial Epithelial Cells Epithelium F-Actin Filament Foundations Functional disorder Goals Health Heart Heart Diseases Homeostasis Human In Vitro Intercalated disc Intercellular Junctions Intermediate Filaments Knowledge Link Maintenance Maps Mechanics Microfilaments Molecular Mus Mutation Myocardium Myofibrils N-Cadherin Property Protein Biochemistry Proteins Research Role Series Signal Transduction Site Structure Testis Time Tissues Work alpha catenin beta catenin cardiogenesis design experience flexibility heart function insight meetings operation plakophilin 2 plakophilins protein complex public health relevance reconstitution research study tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The human heart beats upwards of 100,000 times a day, and contractile forces place unique physical and regulatory demands on the protein complexes that join cardiomyocytes together to form a functional heart muscle. Mechanical coupling and chemical communication between cardiomyocytes is accomplished through a specialized adhesive structure called the intercalated disc (ICD). The ICD comprises adherens junctions and desmosomes that connect the actin and intermediate filament cytoskeletons, respectively, to the plasma membrane. ICD formation requires multiple adhesion and cytoskeletal proteins, and mutations in these proteins can cause cardiomyopathies. However, little is known about how these adhesive complexes are assembled or regulated to withstand the forces of cardiomyocyte contraction and maintain tissue integrity. Determining how protein complexes function at the ICD to maintain adhesive homeostasis is critical for understanding heart function and disease. The core of the adherens junction is the cadherin-catenin complex, which is connected to the actin cytoskeleton through α-catenin. α-Catenin is multifunctional actin-binding protein that localizes to the ICD in cardiomyocytes, and loss of α-catenin function in mice causes cardiomyopathy. However, α-catenin functions in cell-cell adhesion in cardiomyocytes are poorly understood. We hypothesize that α-catenin regulates cardiomyocyte cell-cell adhesion by coupling actin and intermediate filaments to ICD junctional complexes. In this proposal, we seek to 1) define how actomyosin tension regulates adherens junction assembly and organization in cardiomyocytes; 2) identify how the molecular properties of αT-catenin, a largely uncharacterized α-catenin expressed in the heart, regulate adherens junction organization and linkage to the actomyosin network; and 3) determine how αT-catenin links to actin and intermediate filament cytoskeletons to regulate cardiomyocyte adhesion. Our work will develop new tools and acquire new knowledge about the molecular mechanisms of cell-cell adhesion in cardiomyocytes, which in turn will provide the foundation for assessing the impact of mutations in ICD proteins on cardiac pathophysiology and inform the development of new strategies for the treatment of cardiomyopathies.