Investigating the Role of Macrophages in Heart Failure with Preserved Ejection Fraction

研究巨噬细胞在射血分数保留的心力衰竭中的作用

基本信息

批准号：
10449478
负责人：
Niranjana Natarajan
金额：
$ 16.39万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449478
关键词：
Age Animal Model Biological Markers Biology Blood Vessels C3AR1 gene Cardiac Cardiology Cardiovascular Diseases Cardiovascular system Career Mobility Cells Clinical Clinical Research Clinical Trials Collaborations Committee Members Complement Complement 3 Complement 3a Complement Activation Complex Data Development Plans Diabetes Mellitus Dichloromethylene Diphosphonate Disease EFRAC Environment Enzyme-Linked Immunosorbent Assay Epidemic Exhibits Extracellular Matrix Failure Fellowship Fibroblasts Fibrosis Flow Cytometry Four-Dimensional Echocardiography Functional disorder Gene Expression Glucose Intolerance Goals Grant Heart Heart failure High Fat Diet Histology Hypertension IL6 gene Immune Immunology In Vitro Infiltration Inflammasome Inflammation Inflammatory Inflammatory Response Institute of Medicine (U.S.)Investigation Knowledge Laboratories Left Ventricular Ejection Fraction Left Ventricular Remodeling Left ventricular structure Liposomes Measures Mediating Mentors Mentorship Metabolic syndrome Modeling Molecular Mus Myocardial Infarction Myofibroblast Natural Immunity Obesity Pathologic Pathology Pathway interactions Patients Phase Phenotype Physiology Pilot Projects Plasma Play Population Positioning Attribute Rattus Regulation Research Research Activity Research Personnel Resolution Resources Role Sampling Signal Transduction Stress Symptoms Syndrome Systems Biology Testing Time Training United States Universities Up-Regulation Ventricular Work Writing arm base career development chemokine cobra venom factor comorbidity complement pathway complement system confocal imaging coronary fibrosis cytokine dietary endothelial dysfunction evidence base experimental study frontier gene complementation improved macrophage new therapeutic target novel post-doctoral training preservation receptor systemic inflammatory response therapeutic target transcriptomics

项目摘要

CHALLENGE: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome that presents with heart failure symptoms, unaltered left ventricular ejection fraction, and is associated with comorbidities including obesity, diabetes and metabolic syndrome. HFpEF accounts for ~50% of all heart failure (HF) and is characterized by diastolic dysfunction and extensive cardiac fibrosis. The pathophysiology of HFpEF is not well understood, and there are no evidence-based therapies to treat HFpEF. In pilot studies, we utilized two-independent HFpEF models – i) 2-hit HFpEF model of hypertension and high-fat diet in mice and ii) obese ZSF1 rats. Both HFpEF models exhibit diastolic dysfunction, obesity and glucose intolerance. In the mouse HFpEF model, we observed increased numbers of inflammatory cells in the heart. We also observed an increase in fibroblast differentiation into myofibroblasts, upregulation of extracellular matrix (ECM) genes and complement signaling in the hearts HFpEF mice. We hypothesize that exaggerated macrophage infiltration into the left ventricle (LV) mediates pathological cardiac remodeling in HFpEF by modulating cardiac fibroblast differentiation and function. GOAL: Here, we propose to investigate the mechanisms by which inflammatory macrophages cause cardiac remodeling in HFpEF at the cellular, molecular and functional levels. In Aim 1, we will investigate the mechanisms by which inflammatory macrophages mediate fibroblast differentiation. We will also assess the contribution of macrophages to cardiac remodeling and diastolic dysfunction in two independent HFpEF models by depleting macrophages with clodronate liposomes. In Aim 2, we will determine the effect of complement signaling on macrophage polarization. We will characterize cardiac macrophage populations in HFpEF models after complement depletion and examine the role of NLRP3 inflammasome activation in cardiac fibroblast function. The long-term goal of this study is to understand the molecular basis of inflammation-mediated cardiac remodeling in HFpEF. To facilitate my transition from a mentored postdoctoral fellowship to a stable independent research position, the K99 phase will be conducted as integrated mentored career development and research activities, and the R00 phase will be devoted to execution of the proposed research, establishing collaborations, and writing a DP2 and an R01 grant. INNOVATION: The proposed work pushes the envelope on multiple novel frontiers. It aims to uncover mechanisms at the molecular, cellular and functional levels of organization. It integrates two orthogonal fields – intercellular signaling in cardiovascular disease and regulation of fibroblast function by inflammatory signals. Our studies will for the first time characterize inflammatory signals that mediate fibroblast activation and cardiac remodeling in HFpEF. Understanding these mechanisms will help identify therapeutic targets to mitigate cardiac remodeling in HF.

挑战：保留射血分数（HFPEF）的心力衰竭是一种复杂的临床综合征出现心力衰竭症状，未改变的左心室射血分数，与合并症，包括肥胖，糖尿病和代谢综合征。 HFPEF占所有心力衰竭的约50％（HF），其特征是舒张功能障碍和广泛的心脏纤维化。 HFPEF的病理生理学没有很好的理解，也没有循证疗法来治疗HFPEF。在试点研究中，我们利用了两种独立的HFPEF模型 - i）小鼠和ii）肥胖的高血压和高脂饮食的2击HFPEF模型 ZSF1大鼠。这两种HFPEF模型均表现出舒张功能障碍，肥胖和葡萄糖肠。在鼠标中 HFPEF模型，我们观察到心脏中炎性细胞数量增加。我们还观察到增加在成纤维细胞分化为肌纤维细胞中，细胞外基质（ECM）基因的上调和完成心脏发出信号HFPEF小鼠。我们假设夸张的巨噬细胞渗入左侧通风（LV）通过调节心脏成纤维细胞分化来介导HFPEF中的病理心脏重塑和功能。目标：在这里，我们建议研究炎症巨噬细胞引起心脏的机制在细胞，分子和功能水平的HFPEF中进行重塑。在AIM 1中，我们将研究机制炎症巨噬细胞介导成纤维细胞分化。我们还将评估巨噬细胞通过耗尽两个独立的HFPEF模型中心脏重塑和舒张功能障碍巨噬细胞具有氯膦酸盐脂质体。在AIM 2中，我们将确定完成信号的影响巨噬细胞极化。我们将在HFPEF模型中表征心脏巨噬细胞种群补体耗竭并检查NLRP3炎性体激活在心脏成纤维细胞功能中的作用。这项研究的长期目标是了解炎症介导的心脏的分子基础在HFPEF中进行改建。促进我从心理的博士后奖学金过渡到稳定的独立研究职位，K99阶段将作为综合事业发展和研究进行活动，R00阶段将致力于执行拟议的研究，建立合作，并撰写DP2和R01赠款。创新：拟议的工作将信封推向了多个新颖的边界。它旨在揭露组织分子，细胞和功能水平的机制。它整合了两个正交字段 - 心血管疾病中的细胞间信号传导以及通过炎症信号调节成纤维细胞功能。我们的研究将首次表征介导成纤维细胞激活和心脏的炎症信号在HFPEF中进行改建。了解这些机制将有助于识别治疗靶点以减轻心脏在HF中进行改建。