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

• 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
• 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

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：射血分数保留性心力衰竭（HFpEF）是一种复杂的临床综合征， 出现心力衰竭症状，左心室射血分数不变，并与 合并症包括肥胖症、糖尿病和代谢综合征。HFpEF占所有心力衰竭的约50% (HF)其特征在于舒张功能障碍和广泛的心脏纤维化。HFpEF的病理生理学 尚不清楚，也没有循证疗法来治疗HFpEF。在试点研究中，我们利用 两个独立的HFpEF模型- i）小鼠中高血压和高脂肪饮食的2次击中HFpEF模型和ii）肥胖 F1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。小鼠 在HFpEF模型中，我们观察到心脏中炎性细胞数量增加。我们还观察到 在成纤维细胞分化成肌成纤维细胞中，细胞外基质（ECM）基因和补体 HFpEF小鼠心脏中的信号传导。我们假设巨噬细胞过度浸润到左侧 心室（LV）通过调节心脏成纤维细胞分化介导HFpEF中的病理性心脏重塑 和功能 目标：在这里，我们建议研究炎症巨噬细胞引起心脏损害的机制。 HFpEF在细胞、分子和功能水平的重构。在目标1中，我们将研究 炎性巨噬细胞通过其介导成纤维细胞分化。我们还将评估 在两个独立的HFpEF模型中，通过消耗 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模型中表征心脏巨噬细胞群， 补体消耗和检查NLRP 3炎性体活化在心脏成纤维细胞功能中的作用。 本研究的长期目标是了解炎症介导的心脏 HFpEF中的重构。为了帮助我从一个有指导的博士后奖学金过渡到一个稳定的独立研究生， 研究职位，K99阶段将作为综合辅导职业发展和研究进行 活动，R 00阶段将致力于执行拟议的研究，建立合作， 写DP 2和R 01授权。 创新：拟议的工作推动了多个新领域的信封。它旨在揭示 在分子、细胞和功能组织水平上的机制。它整合了两个正交的领域- 心血管疾病中的细胞间信号传导和炎症信号对成纤维细胞功能的调节。我们 研究将首次描述介导成纤维细胞活化和心脏炎症的炎症信号。 HFpEF中的重构。了解这些机制将有助于确定治疗靶点，以减轻心脏病 HF的重塑