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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：射血分数保留的心力衰竭 (HFpEF) 是一种复杂的临床综合征，出现心力衰竭症状，左心室射血分数未改变，并且与合并症包括肥胖、糖尿病和代谢综合征。 HFpEF 约占所有心力衰竭的 50% （HF），其特征是舒张功能障碍和广泛的心脏纤维化。 HFpEF 的病理生理学目前尚不清楚，并且没有治疗 HFpEF 的循证疗法。在试点研究中，我们利用两个独立的 HFpEF 模型 – i) 小鼠高血压和高脂肪饮食的 2-hit HFpEF 模型和 ii) 肥胖 ZSF1 大鼠。两种 HFpEF 模型均表现出舒张功能障碍、肥胖和葡萄糖耐受不良。在鼠标中在 HFpEF 模型中，我们观察到心脏中炎症细胞数量增加。我们还观察到增加在成纤维细胞分化为肌成纤维细胞、细胞外基质 (ECM) 基因和补体上调 HFpEF 小鼠心脏中的信号传导。我们假设巨噬细胞过度浸润左侧心室 (LV) 通过调节心脏成纤维细胞分化介导 HFpEF 的病理性心脏重塑和功能。目标：在这里，我们建议研究炎症巨噬细胞引起心脏病的机制 HFpEF 在细胞、分子和功能水平上的重塑。在目标 1 中，我们将研究其机制炎症巨噬细胞通过其介导成纤维细胞分化。我们还将评估以下人员的贡献巨噬细胞通过消耗在两个独立的 HFpEF 模型中对心脏重塑和舒张功能障碍的影响巨噬细胞与氯膦酸盐脂质体。在目标 2 中，我们将确定补体信号传导对巨噬细胞极化。我们将在 HFpEF 模型中描述心脏巨噬细胞群的特征补体耗竭并检查 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疾病的分子基础 HFpEF 中的重塑。为了促进我从指导博士后奖学金过渡到稳定的独立博士后奖学金研究职位，K99阶段将作为综合指导的职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 补助金。创新：拟议的工作挑战了多个新颖前沿的极限。其目的是揭开组织的分子、细胞和功能水平的机制。它整合了两个正交领域—— 心血管疾病中的细胞间信号传导以及炎症信号对成纤维细胞功能的调节。我们的研究将首次表征介导成纤维细胞活化和心脏功能的炎症信号 HFpEF 中的重塑。了解这些机制将有助于确定减轻心脏病的治疗靶点高频重塑。