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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：
10297260
负责人：
Adam Vincent Kwiatkowski
金额：
$ 39.94万
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 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297260
关键词：
Actin-Binding Protein Actins Adaptor Signaling Protein Adherens Junction Adhesions Adhesives Affect Allosteric Regulation Architecture Binding Biochemical Biochemistry Biological Cadherins Cardiac Myocytes Cardiomyopathies Cell Adhesion Cell Communication Cell-Cell Adhesion Cells Cellular biology Collection Complex Coupling Cues Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Data Desmosomes Development Epithelial Equilibrium Extracellular Matrix Foundations Goals Grant Health Heart Heart Diseases Homeostasis Human In Situ Individual Intercalated disc Intermediate Filaments Knowledge Lead Ligand Binding Ligands Link Maintenance Mechanics Mediating Membrane Microfilaments Molecular Mutation Myofibrils Outcome Output Peripheral Property Proteins Proteomics Publishing Research Role Series Signal Transduction Structure System Testis Thermodynamics Tissues Vinculin Work alpha catenin cardiogenesis design experimental study heart function insight link protein mechanical force operation protein complex reconstitution recruit response tool treatment strategy

项目摘要

Project Summary With every heartbeat, the junctional complexes that couple cardiomyocytes must transmit the mechanical forces of contraction while maintaining adhesive homeostasis. Cardiomyocytes are linked end-to-end by the intercalated disc (ICD), a specialized junction that coordinates cell signaling, electrical and mechanical operations. The ICD comprises adherens junctions (AJs) and desmosomes that connect the actin and intermediate filament cytoskeletons, respectively, of adjoining cells. ICD function requires multiple adhesion and cytoskeletal proteins and mutations in these proteins are linked to cardiomyopathies. However, relatively little is known about how adhesion complexes are regulated to establish and maintain heart tissue integrity. The core of the adherens junction is the cadherin-catenin complex, which is connected to the actin cytoskeleton through a-catenin. a-Catenin is a multifunctional, mechanoresponsive actin-binding protein that localizes to the cardiomyocyte ICD. However, a-catenin functions in cell-cell adhesion in cardiomyocytes are poorly understood. Our objective in this application is to determine how mechanical and molecular inputs are transduced through the two a-catenins expressed in the human heart – aE(Epithelial)-catenin and aT(Testes)- catenin – to regulate cardiomyocyte adhesion. Our rationale is that defining the individual and collective roles of a-catenin at cardiomyocyte AJs will provide fundamental insight into how cardiomyocyte AJs balance mechanical and signaling functions. We hypothesize that aE-catenin and aT-catenin form unique cadherin- catenin complexes in response to cellular cues to function as mechanical checkpoints for ICD assembly and cardiomyocyte organization. In this proposal, we seek to: 1) define the allosteric mechanisms that regulate a- catenin ligand binding at the cardiomyocyte AJ; 2) determine how ligand recruitment to a-catenin promotes AJ assembly and cytoskeletal attachment; and 3) identify how external mechanical cues regulate AJ organization. Knowledge to be gained through our studies include a detailed, mechanistic understanding of how a-catenin molecular properties are tuned for adhesion in cardiomyocytes; how unique molecular complexes are built along the cardiomyocyte AJ to establish and maintain adhesion; and how external mechanical cues feed into the cardiomyocyte AJ to drive organization. This comprehensive, multiscale analysis will develop new tools and acquire new knowledge about the molecular mechanisms of cell adhesion in cardiomyocytes. Understanding the fundamental mechanisms of cell adhesion in cardiomyocytes is necessary for determining how mutations in ICD proteins lead to heart disease and inform the development of new strategies for the treatment of cardiomyopathies.

项目总结