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

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 包括肥胖、糖尿病和代谢综合征在内的合并症。HFpEF占所有心力衰竭的50%左右 (心衰),以舒张期功能障碍和广泛的心脏纤维化为特征。HFpEF的病理生理学研究 目前尚不清楚,也没有治疗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)2次打击的高血压和高脂饮食的HFpEF模型和II)肥胖 ZSF1大鼠。两种HFpEF模型均表现为舒张期功能障碍、肥胖和糖耐量减低。在鼠标中 在HFpEF模型中,我们观察到心脏中炎性细胞的数量增加。我们也观察到了增加 成纤维细胞向肌成纤维细胞分化过程中细胞外基质(ECM)基因和补体的上调 HFpEF小鼠心脏中的信号。我们假设夸大的巨噬细胞渗入左侧 心室(LV)通过调节心脏成纤维细胞分化介导HFpEF病理性心脏重构 和功能。 目的:本研究旨在探讨炎症巨噬细胞引起心脏疾病的机制。 HFpEF在细胞、分子和功能水平的重塑。在目标1中,我们将研究这些机制 炎性巨噬细胞通过其介导成纤维细胞分化。我们还将评估以下方面的贡献 巨噬细胞对两种独立HFpEF模型心脏重构和舒张期功能障碍的影响 巨噬细胞与氯屈膦酸脂质体。在目标2中,我们将确定补体信号在 巨噬细胞极化。我们将在HFpEF模型中表征心脏巨噬细胞的数量 并检测NLRP3炎性小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。 HFpEF的重塑。帮助我从一个有导师的博士后研究员职位转变为一个稳定的独立博士后 研究职位,K99阶段将作为综合指导职业发展和研究进行 活动,R00阶段将专门用于执行拟议的研究,建立合作, 以及写一份DP2和一份R01拨款。 创新:拟议中的工作在多个新的前沿领域推动了极限。它的目的是揭示 分子、细胞和组织功能层面的机制。它集成了两个正交场- 心血管疾病中的细胞间信号和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疾病的炎症信号。 HFpEF的重塑。了解这些机制将有助于确定减轻心脏疾病的治疗靶点 心衰时的重塑。

项目成果

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Niranjana Natarajan其他文献

Niranjana Natarajan的其他文献

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{{ truncateString('Niranjana Natarajan', 18)}}的其他基金

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:
    10629241
  • 财政年份:
    2022
  • 资助金额:
    $ 16.39万
  • 项目类别:
Investigating the role of the complement system in cardiac regeneration
研究补体系统在心脏再生中的作用
  • 批准号:
    10093224
  • 财政年份:
    2019
  • 资助金额:
    $ 16.39万
  • 项目类别:
Investigating the role of the complement system in cardiac regeneration
研究补体系统在心脏再生中的作用
  • 批准号:
    9760060
  • 财政年份:
    2019
  • 资助金额:
    $ 16.39万
  • 项目类别:
Investigating the role of the complement system in cardiac regeneration
研究补体系统在心脏再生中的作用
  • 批准号:
    10176559
  • 财政年份:
    2019
  • 资助金额:
    $ 16.39万
  • 项目类别:

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