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:
- 金额:$ 16.39万
- 依托单位:
- 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:
- 关键词:AgeAnimal ModelBiological MarkersBiologyBlood VesselsC3AR1 geneCardiacCardiologyCardiovascular DiseasesCardiovascular systemCareer MobilityCellsClinicalClinical ResearchClinical TrialsCollaborationsCommittee MembersComplementComplement 3Complement 3aComplement ActivationComplexDataDevelopment PlansDiabetes MellitusDichloromethylene DiphosphonateDiseaseEFRACEnvironmentEnzyme-Linked Immunosorbent AssayEpidemicExhibitsExtracellular MatrixFailureFellowshipFibroblastsFibrosisFlow CytometryFour-Dimensional EchocardiographyFunctional disorderGene ExpressionGlucose IntoleranceGoalsGrantHeartHeart failureHigh Fat DietHistologyHypertensionIL6 geneImmuneImmunologyIn VitroInfiltrationInflammasomeInflammationInflammatoryInflammatory ResponseInstitute of Medicine (U.S.)InvestigationKnowledgeLaboratoriesLeft Ventricular Ejection FractionLeft Ventricular RemodelingLeft ventricular structureLiposomesMeasuresMediatingMentorsMentorshipMetabolic syndromeModelingMolecularMusMyocardial InfarctionMyofibroblastNatural ImmunityObesityPathologicPathologyPathway interactionsPatientsPhasePhenotypePhysiologyPilot ProjectsPlasmaPlayPopulationPositioning AttributeRattusRegulationResearchResearch ActivityResearch PersonnelResolutionResourcesRoleSamplingSignal TransductionStressSymptomsSyndromeSystems BiologyTestingTimeTrainingUnited StatesUniversitiesUp-RegulationVentricularWorkWritingarmbasecareer developmentchemokinecobra venom factorcomorbiditycomplement pathwaycomplement systemconfocal imagingcoronary fibrosiscytokinedietaryendothelial dysfunctionevidence baseexperimental studyfrontiergene complementationimprovedmacrophagenew therapeutic targetnovelpost-doctoral trainingpreservationreceptorsystemic inflammatory responsetherapeutic targettranscriptomics
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
肥胖、糖尿病和代谢综合征等合并症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,并且没有基于证据的疗法来治疗 HFpEF。
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 模型均表现出小鼠舒张功能障碍、肥胖和葡萄糖耐受不良。
在 HFpEF 模型中,我们观察到心脏中炎症细胞数量的增加。
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
我们勇敢地面对 HFpEF 小鼠心脏中的巨噬细胞浸润。
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。
我们还将评估炎症巨噬细胞介导成纤维细胞分化的贡献。
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
在目标 2 中,我们将确定补体信号传导对巨噬细胞的影响。
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 的重塑,以促进我从指导博士后研究员过渡到稳定的独立。
研究职位,K99阶段将作为综合指导的职业发展和研究进行
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。
它整合了两个正交领域——组织的分子、细胞和功能层面的机制。
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。
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
了解 HFpEF 的重塑将有助于确定减轻心脏功能的治疗靶点。
高频重塑。
项目成果
期刊论文数量(0)
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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:
10176559 - 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:
10093224 - 财政年份:2019
- 资助金额:
$ 16.39万 - 项目类别:
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