Mechanotransduction by Melusin in Cardiac Hypertrophy

Melusin 在心脏肥大中的机械转导

基本信息

批准号：
10207763
负责人：
Nathan John Sniadecki
金额：
$ 53.99万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207763
关键词：
3-Dimensional 3D Print Adhesions Affect Animal Model Apoptosis Attenuated Binding Binding Proteins Biological Assay Biomedical Engineering Bioreactors Calcium Cardiac Cardiac Myocytes Cell Size Cells Co-Immunoprecipitations Collaborations Complex Development Dilated Cardiomyopathy Echocardiography Exercise Gap Junctions Gene Expression Goals Growth Head Health Heart Heart Diseases Heart Hypertrophy Heart failure Histology Human Human Engineering Hypertrophic Cardiomyopathy Hypertrophy Impairment Individual Inherited Integrin Binding Integrins Knock-out Length Mass Spectrum Analysis Mechanics Mediating Modeling Molecular Molecular Biology Monitor Mus Mutation Myocardial tissue Myofibrils Organoids PTK2 gene Pathologic Pathway interactions Physiological Physiology Play Pregnancy Proteins Proto-Oncogene Proteins c-akt Reporting Resistance Risk Role Signal Pathway Signal Transduction Signaling Protein Silicones Site Stress Stretching System Tail Testing Tetracyclines Thick Tissues Trans-Activators Transgenic Mice Troponin C Universities Variant Viral Washington Work base cardiac pacing cardiac tissue engineering cardiovascular risk factor constriction exercise training fascinate flexibility hemodynamics induced pluripotent stem cell inherited cardiomyopathy mechanotransduction molecular diagnostics novel overexpression predictive modeling prevent recruit response stem cell biology

项目摘要

PROJECT SUMMARY/ABSTRACT The goal of the proposed work is to determine if melusin acts as a cardiac-specific mechanotransducer in human cardiomyocytes leading to hypertrophy, and unravel the mechanisms leading to activation of this pathway. Myocardial tissue responds to elevated hemodynamic load by hypertrophic growth to increase wall thickness and thereby reduce wall stress. How these loads are transduced by individual cardiomyocytes in the heart is not well understood, but melusin (ITGB1BP2), a β1 integrin binding protein, may play an important role. Melusin forms a signalosome at the costameres of cardiomyocytes and sits at a nexus between two major hypertrophic pathways, ERK and AKT. We hypothesize that it has an autoinhibitory state due to intramolecular interactions that hinder its effect in hypertrophic signaling, but this autoinhibition may be attenuated in response to tension. The specific aims of this proposal will test the effects of melusin on pathological and physiological hypertrophy in transgenic mice, conduct controllable mechanistic studies in human engineered heart tissue, and examine whether intramolecular interactions inhibit its assembly at adhesion sites. These studies will elucidate if melusin plays a role in tension-mediated hypertrophy and verify its response in a human cardiac organoid model and with bioengineering approaches using human induced pluripotent stem cell derived cardiomyocytes. The health impact of this work will identify whether melusin is a key player in hypertrophy and provide a detailed understanding on how melusin affects cardiac growth in response to inherited cardiomyopathies and hemodynamic overload.

项目摘要/摘要支撑工作的目的是确定梅洛蛋白在人类中是否充当心脏特异性机械转换器。心肌细胞导致肥大，并揭示导致该途径激活的机制。心肌组织通过肥厚性生长对血液动力学负荷的升高反应，以增加壁厚从而减少壁压力。良好的理解，但是梅洛蛋白（ITGB1BP2）是β1整联蛋白结合蛋白，可能起重要作用在心肌细胞的成分体处形成信号体，并位于两个主要肥厚型之间的Nexus 途径，ERK和AKT。这阻碍了其在肥厚的信号中的影响该提案的具体目的将测试梅洛素对病理和生理肥大的影响在转基因小鼠中，在人类发动机组织中进行可控的机械研究，并检查分子内是否会抑制其组装位点。在张力介导的肥大中起作用，并在人类心脏器官模型中验证其反应使用人类诱导的多能干细胞衍生的心肌细胞的生物工程方法。世界的影响将确定Melusin是否是肥大的关键参与者，并提供详细的了解梅洛素如何影响遗传性心肌病和血液动力学超负荷。