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Function and Mechanism of the Intercalated Disc Protein XinB in Cardiomyocyte Proliferation and Cardiac Regeneration

闰盘蛋白XinB在心肌细胞增殖和心脏再生中的作用及机制

基本信息

批准号：
10681642
负责人：
Da-Zhi Wang
金额：
$ 56.36万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681642
关键词：
Adaptor Signaling Protein Adherens Junction Adult Affect Age Binding Biochemical Biological Process Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell Nucleus Cell Proliferation Cells Complex DNA Sequence Alteration Defect Development Disease Elderly Feedback Gene Expression Gene Targeting Genes Genetic Genetic Transcription Giant Cells Healthcare Heart Heart Abnormalities Heart Diseases Human Impairment Incidence Intercalated disc Intercellular Junctions Knock-out Knockout Mice Link Location Maintenance Malignant Neoplasms Mechanics Mediating Molecular Mutant Strains Mice Myocardial Contraction Myocardium N-Cadherin Natural regeneration Neurofibromin 2 Nodal Pathogenesis Pathway interactions Patients Phosphorylation Play Population Process Proliferating Protein Kinase Proteins Publishing Regulation Regulatory Pathway Reporting Repression Role Series Signal Transduction Structure Subcellular structure System Testing Therapeutic Intervention Translations Work beta catenin cardiac regeneration cardiogenesis cell growth cofactor design heart function human disease new therapeutic target novel overexpression paralogous gene postnatal programs success targeted treatment therapy development tissue repair transcription regulatory network transmission process

项目摘要

ABSTRACT Cardiovascular diseases remain the leading cause of death in humans, yet the molecular mechanisms underlying these devastating conditions have not been fully elucidated. Cardiac disease is especially common in the elderly, and as the global population ages their elevated incidence will pose a serious healthcare challenge. An important structure in heart muscle cells is the intercalated disc (ICD), which mediates the coordination of the cardiac syncytium. It functions by connecting neighboring cardiomyocytes, thereby maintaining the functional integrity of this syncytium; this is crucial to the proper contraction of the heart. Although many reports demonstrate the importance of ICDs in the organization of the myocardium, relatively little is known about how these cell-to-cell junctions transmit information between cardiac muscle cells to modulate gene expression and cardiac function. The Xin-repeat containing adaptor proteins Xinα and Xinβ, also called XIRP1 and XIRP2 respectively, were first discovered by the PI. These two proteins are located in the ICD of adult cardiomyocytes and interact with various adherens junction proteins including N-cadherin and β-catenin, supporting an essential role for them in the formation/maintenance of this structure. They also play important roles during early cardiac development and in the pathogenesis of heart disease. However, the role of the Xin proteins remains poorly studied and their specific cellular and molecular functions are largely unknown. Our recent studies of the hearts of Xin knock-out (KO) mice have identified defects in development associated with impaired cardiomyocyte proliferation. Our studies further demonstrated a physical and genetic interaction between Xin and NF2, a component of the important Hippo/YAP pathway. The Hippo-YAP pathway is a highly conserved cellular regulatory network that has been previously implicated in multiple developmental systems and disease, including the heart; however, the mechanisms of its action remain unclear and a link to the ICD is a novel and exciting new discovery. Therefore, we have designed two integrative Specific Aims to test the mechanism by which the ICD protein Xin mediates cardiomyocyte proliferation, maturation, and regeneration. For the first Aim, we will investigate the interaction between Xin and the Hippo/YAP pathway. We will study how Xin regulates YAP activity and how the interaction between Xin and Hippo-YAP signaling regulates cardiac function and regeneration. For the second Aim, we will study how YAP/Tead1 regulates Xin transcription and test our hypothesis that Xin-YAP cross-regulation is crucial to cardiac gene expression and heart regeneration. The studies proposed here will reveal novel molecular mechanisms by which the important pathophysiological Hippo/YAP signal is modulated by the ICD protein Xin in the heart. The molecules defined in this study will become targets for therapeutic intervention in the treatment of cardiac diseases.

摘要