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Osteopontin Signals between Myocytes and Fibroblasts to Regulate Cardiac Remodeling

肌细胞和成纤维细胞之间的骨桥蛋白信号调节心脏重塑

基本信息

批准号：
9336424
负责人：
Lina A Shehadeh
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336424
关键词：
Adhesions Aging Angiotensin II Attenuated Binding Blood Circulation CD44 gene Cardiac Cardiac Myocytes Cardiovascular system Catheterization Cells Cessation of life Chronic Chronic Kidney Failure Data Development Dyspnea Echocardiography Exhibits Extracellular Matrix Extracellular Matrix Proteins FRAP1 gene Fatigue Fibroblasts Fibronectins Fibrosis Functional disorder Gene Deletion Genetic Models Goals Health Heart Heart Diseases Heart Hypertrophy Heart failure Histopathology Hypertrophy In Vitro Injection of therapeutic agent Integrins Knock-out Knockout Mice Label Lead Left Left Ventricular Remodeling Liquid substance Mass Spectrum Analysis Methods Modeling Mus Muscle Cells Myocardial Infarction Myocardial dysfunction Myofibroblast Neonatal Neurosecretory Systems Paracrine Communication Pathway interactions Patients Phosphorylation Physiological Play Property Proteins Proto-Oncogene Proteins c-akt Public Health Pump RNA RNA-Binding Proteins Regulation Research Role Signal Transduction Signaling Protein Staging Stress System Therapeutic Agents Thrombospondin 1 Ventricular Ventricular Remodeling aptamer cardiovascular injury constriction coronary fibrosis cytokine extracellular improved in vivo interest interstitial member migration mortality mouse model novel novel therapeutic intervention novel therapeutics osteopontin outcome forecast pressure prevent protein expression receptor response

项目摘要

DESCRIPTION (provided by applicant): Heart failure is the common end-stage for cardiac disease and is a problem of major public health significance. Despite longstanding research into the basic mechanisms underlying pathological remodeling and heart failure, current therapies remain inadequate, and 5-year mortality for heart failure remains at 50%. Recently, there has been increasing interest in the role of cardiac fibroblasts in ventricular remodeling, including ho cardiac fibroblasts respond to paracrine signals originating in the stressed myocyte. Understanding how cardiac fibroblasts and myocytes together contribute to remodeling resulting in heart failure should lead to new therapeutic strategies that will improve the prognosis for those with chronic cardiovascular conditions. Osteopontin (OPN) is a secreted protein that signals between cardiac myocytes and fibroblasts. OPN plays pivotal roles in the regulation of proliferation, survival, adhesion, and migration of cells by signaling through integrin and CD44 receptors. OPN expression is highly induced in heart failure. Using a constitutive, global knockout mouse, OPN has been shown to promote the interstitial myocardial fibrosis induced by pressure overload8 or myocardial infarction (MI). Similarly, by gene deletion, CD44 has been found to promote fibroblast proliferation in vivo after MI and in vitro. However, the cellular mechanisms conferring OPN-CD44 signaling in cardiac remodeling remain unknown. We have recently developed a novel method by which to block OPN function, in vivo injection of a protein-binding RNA molecule called OPN RNA aptamer. Using the OPN RNA aptamer, we have confirmed that OPN is required for pressure overload-induced left ventricular remodeling. Moreover, aptamer injection attenuated the development of heart failure. Inspired by these results, the goal of this application is to explore the cell autonomous mechanisms by which OPN contributes to interstitial fibrosis. By mass spectroscopy, we have identified novel OPN binding partners, including extracellular matrix proteins Fibronectin-1 (FN1) and Thrombopondin-1 (TSP1), CD44 receptors, and members of the PI3K/Akt/mTOR pathway. Our central hypothesis is that the binding of cardiac OPN to CD44 receptors on cardiac fibroblasts and/or myocytes is essential for ventricular remodeling. We propose that secreted OPN interacts with extracellular TSP1/FN1, binds to CD44 receptors, and activates PI3K/Akt signaling resulting in myofibroblast differentiation and myocyte hypertrophy.