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Determining the Role of GRK5 in Cardiac Fibroblasts

确定 GRK5 在心脏成纤维细胞中的作用

基本信息

批准号：
9918158
负责人：
Akito Eguchi
金额：
$ 5.05万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918158
关键词：
Actins Acute Address Adult Angiotensin II Attenuated Cardiac Cardiac Myocytes Cardiac Output Cardiovascular system Cell Nucleus Cells Chronic Clinical Collagen Complement Factor B Contracts Data Deposition Disease Disease Progression Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GRK5 gene Gene Proteins Genetic Genetic Transcription Genetically Engineered Mouse Goals Healthcare Heart Heart Hypertrophy Heart Injuries Heart failure Homeostasis Human Impairment In Vitro Injury Interdisciplinary Study Knock-out Knockout Mice MMP2 gene Mechanics Mediator of activation protein Metabolic Modeling Mus Muscle Myocardial Infarction Myofibroblast Nuclear Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Phosphotransferases Physiological Physiology Population Process Public Health Research Role Signal Pathway Smooth Muscle Actin Staining Method Stress Structure Syndrome Therapeutic Transforming Growth Factors Translating United States base blood pump cardioprotection cell type clinically relevant coronary fibrosis effective therapy healing heart function improved in vivo in vivo Model insight knock-down loss of function mortality novel nuclear factors of activated T-cells overexpression prevent programs response response to injury transcription factor transdifferentiation translational approach

项目摘要

Project Summary Heart Failure (HF) is a clinical syndrome that is the leading cause of mortality in the United States. It is characterized by the heart’s inability to pump blood sufficiently to meet the metabolic demands of the body. Pathological remodeling of the heart is a hallmark of HF and these gross changes in the structure of the heart further perpetuates the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the structural integrity of the heart. Stress conditions, such as a myocardial infarction, activate and induce the transdifferentiation of quiescent fibroblasts into synthetic and contractile myofibroblasts. While required for the initial healing response, sustained myofibroblast activation leads to over-secretion of extracellular matrix proteins which promotes fibrosis. Furthermore, de novo expression of -smooth muscle actin allows these cells to contract, disrupting coordinated cardiomyocyte contractility. These structural and mechanical changes to the heart impair cardiac function. G protein-coupled receptor (GPCR) kinases (GRKs) are important mediators of cardiovascular homeostasis through dampening of GPCR signaling. Recently, non-canonical activities of these GRKs have been elucidated. GRK5 has been demonstrated to translocate to the nucleus in cardiomyocytes, promoting hypertrophic gene transcription through activation of nuclear factor of activated T- cells (NFAT) and nuclear factor B (NFB). Interestingly, these transcription factors are also involved in fibroblast activation and transdifferentiation. Our preliminary data strongly suggests a critical role for GRK5 in the activation and transdifferentiation of fibroblasts. The long-term research goal is to elucidate novel insight into the complexity of HF and associated cardiac remodeling as well as the role of GRK5 in this process. The specific aims are as follows: (1) To assess the role of GRK5 in fibroblast activation and transdifferentiation in vitro and (2) To assess the role of fibroblast GRK5 in cardiac fibrosis and HF progression after myocardial infarction in vivo. Specific aim 1 will be conducted using overexpression and knockout models of GRK5 in cardiac fibroblasts. These fibroblasts will be treated with Angiotensin II (AngII) and Transforming Growth Factor  to induce differentiation. Specific aim 2 will utilize fibroblast specific GRK5 knockout mice which will undergo myocardial infarction surgery to mimic a clinically relevant disease. Accomplishment of these specific aims will provide novel understanding of fibroblast physiology and GRK5’s role in fibroblast activation/transdifferentiation. In terms of public health, targeting of cardiac fibroblasts provides a novel translational approach for the treatment of HF and cardiac fibrosis.

项目总结