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Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after cardiac injury

靶向心脏成纤维细胞-肌细胞的串扰以增强心脏损伤后的心脏功能

基本信息

批准号：
10471907
负责人：
Arjun Deb
金额：
$ 54.6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2020-09-02 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471907
关键词：
Acute Affect Animals Area Attenuated Biochemical Cardiac Cardiac Myocytes Cardiovascular system Cell Death Cells Cicatrix Collaborations Data Dilatation - action Diphosphates Endothelial Cells Event Fibroblasts Fibrosis Genetic Goals Heart Heart Injuries Hour Infarction Infiltration Inflammation Inflammatory Integral Membrane Protein Mediating Mediator of activation protein Metabolic Molecular Molecular Mechanisms of Action Monoclonal Antibodies Muscle Cells Myocardial Infarction Myocardial dysfunction Myocardium Natural regeneration Necrosis Nuclear Magnetic Resonance Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Physiological Play Population Proliferating Proteins Public Health Research Personnel Role Signal Transduction Smooth Muscle Myocytes Structure Testing Therapeutic Time Tissues Ventricular calcification cardiac repair cell type cytokine extracellular heart function hemodynamics injured ischemic injury loss of function macrophage metabolomics monocyte myocardial injury neutrophil novel plasma cell membrane glycoprotein PC-1 preservation pyrophosphatase repair function repaired response to injury single-cell RNA sequencing small molecule small molecule inhibitor spatiotemporal stem cells treatment strategy wound healing

项目摘要

Project Summary/Abstract Cardiac repair following ischemic myocardial injury involves a carefully orchestrated set of cellular events. The cardiac cell population substantially changes after cardiac injury with infiltration of initially neutrophils, then macrophages and robust proliferation of fibroblasts and endothelial cells. Cell-cell cross talk undoubtedly affects cardiac wound healing but little is known about whether cell-cell cross talk can be targeted for enhancing cardiac repair. In this proposal, we identify an unusual cross talk between myocytes and non- myocytes that regulates cardiac wound healing. We demonstrate that cardiac fibroblasts dramatically upregulate the protein ENPP1 (ectonucleotide pyrophosphatase 1) following ischemic cardiac injury. ENPP1 hydrolyzes extracellular ATP and we show that ATP hydrolytic products induces myocytes to release metabolites that are pro-inflammatory and induce cell death of various non-myocyte cells regulating wound healing such as macrophages, endothelial cells, fibroblasts and smooth muscle cells. We identify such myocyte secreted pro-inflammatory metabolites and investigate molecular mechanisms of action of such metabolites on non-myocyte cells. We provide preliminary data that genetic deletion of ENPP1 in cardiac fibroblasts dramatically ameliorates post injury heart function and is associated with decreased scarring and decreased post injury cardiac dilatation. We identify small molecule inhibitors of ENPP1 as well as monoclonal antibodies targeting ENPP1 and demonstrate that pharmacologic targeting of ENPP1 can serve as a therapeutic strategy for post infarction cardiac remodeling. These observations form a rational basis for investigating in depth the physiological significance of ENPP1 mediated myocyte-non myocyte cross talk in cardiac repair and determine whether pharmacologic targeting of ENPP1 mediated fibroblast-non myocyte cross talk is potentially a therapeutic strategy for ischemic cardiac injury.

项目总结/文摘