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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：
10238764
负责人：
Michelle D Tallquist
金额：
$ 53.88万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238764
关键词：
Ablation Acute Anti-Inflammatory Agents 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 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 immune activation 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.

摘要心力衰竭是一种进行性疾病，通常因不适当的心脏重塑而加重，对压力的反应。然而，可以有效靶向纤维化的疗法，病理性重塑，目前还无法获得。虽然急性损伤后的炎症反应是对于清除死亡组织至关重要，并且一些纤维化可能是必要的，以保持张力由于受损心肌的强度，持续的炎症反应可导致不适当的纤维化程度。几种常驻心脏细胞群与调节心肌细胞的增殖有关。急性心脏损伤后免疫细胞的组成和活化，但心脏成纤维细胞的作用在这一过程中，人们知之甚少。这些研究的目的是阐明成纤维细胞在在调节炎症中发挥作用。我们的初步数据表明，最初的先天免疫在没有成纤维细胞的情况下，反应正常进行，但炎性细胞群比存在成纤维细胞时持续更长时间。我们假设Ras信号在心肌细胞中成纤维细胞在重塑过程中指导抗炎基因表达，这些途径的相互作用将允许致病性和再生性重塑的分化。在Aim I中，我们将使用心脏成纤维细胞消融来确定抗炎信号的时间。然后我们将确定特定的抗炎调节剂。在Aim II中，我们将操纵Ras信号，成纤维细胞，以确定该途径的改变如何控制炎性细胞浸润，活化，以及随后的重塑在目标III中，我们将确定这些炎症调节因子是否在人心脏成纤维细胞中保守。该项目将提供新的见解的作用，心脏成纤维细胞在心脏损伤后的免疫调节中发挥作用，并识别出可以在治疗上调节以限制病理性重塑。