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Regulation of cardiac inflammation by fibroblasts

成纤维细胞调节心脏炎症

基本信息

批准号：
9762629
负责人：
Michelle D Tallquist
金额：
$ 59.04万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-11 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762629
关键词：
Ablation Acute Anti-inflammatory Biological Assay Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cells Cicatrix Data Deposition Drug Targeting Extracellular Matrix Fibroblasts Fibrosis Fluorescence-Activated Cell Sorting Gene Expression Genes Genetic Glean Goals Heart Heart Diseases Heart Injuries Heart failure Human Immune Immune Cell Activation Impairment In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Innate Immune Response Intervention Lead Learning Maintenance Mechanics Mediating Modeling Molecular Molecular Genetics Mus Myocardial Infarction Myocarditis Myocardium Organ Outcome Study Pathogenicity Pathologic Pathway interactions Phase Phenotype Play Population Process Progressive Disease Reagent Regulation Relaxation Repression Resolution Role Signal Pathway Signal Transduction Signal Transduction Pathway Stress Tensile Strength Testing Therapeutic Therapeutic Intervention Time Tissues Transcript Ventricular Work coronary fibrosis experimental study heart function immunoregulation in vivo injured insight molecular marker novel recruit regenerative response response to injury tool

项目摘要

Abstract Heart failure is a progressive disease that is often exacerbated by inappropriate cardiac remodeling in response to stress. However, therapies that can efficiently target fibrosis, a key component of pathologic remodeling, are currently unavailable. While an inflammatory response after acute injury is essential for clearing dead tissue, and some fibrosis may be necessary to maintain the tensile strength of injured myocardium, a sustained inflammatory response can lead to inappropriate amounts of fibrosis. Several resident cardiac cell populations have been implicated in regulating the composition and activation of immune cells after acute heart injury, but the role of cardiac fibroblasts in this process is poorly understood. The goal of these studies is to elucidate the role that fibroblasts play in regulating inflammation. Our preliminary data demonstrate that initial innate immune responses proceed normally in the absence of fibroblasts, but populations of inflammatory cells persist longer than when in the presence of fibroblasts. We hypothesize that Ras signaling in cardiac fibroblasts directs anti-inflammatory gene expression later in the remodeling process and identification of these pathways will permit the differentiation of pathogenic and regenerative remodeling. In Aim I, we will use cardiac fibroblast ablation to identify the timing of anti-inflammatory signals. We will then determine the specific anti-inflammatory regulators. In Aim II, we will manipulate Ras signaling in fibroblasts to determine how alteration of this pathway controls inflammatory cell infiltration, activation, and subsequent remodeling. In Aim III, we will determine if these inflammatory regulators are conserved in human cardiac fibroblasts. This project will provide novel insights into the role that cardiac fibroblasts play in immune regulation after cardiac injury, and identify signaling pathways that may be therapeutically modulated to limit pathologic remodeling.

摘要