Resolvin D1 resolves inflammation in metabolic stress associated HFpEF
Resolvin D1 解决代谢应激相关 HFpEF 中的炎症
基本信息
- 批准号:10533087
- 负责人:
- 金额:$ 24.49万
- 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:2022-09-13 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAge-MonthsAnimal ModelApoptosisApoptoticApplied ResearchAttenuatedAutomobile DrivingBindingBiometryBloodBone MarrowCardiacCardiac MyocytesCardiovascular systemCell NucleusCellsChronicClinicalComplexCoronaryDevelopmentDiabetes MellitusDiagnosisEFRACExercise ToleranceExudateFPR2 geneFailureFibrosisFunctional disorderGene ExpressionGenesGoalsHeartHeart failureHomeostasisHospitalizationHumanHypertensionHypertrophyIncidenceInfiltrationInflammationInflammatoryInnovative TherapyLeukocytesLipoxinsMERTK geneMacrophage ActivationMeasuresMediatingMediator of activation proteinMetabolicMetabolic DiseasesMetabolic stressModelingMonitorMusMyocardialMyocarditisNon-Insulin-Dependent Diabetes MellitusObesityOutcomeOxidative StressPathogenesisPatientsPhenotypePhysiologicalProcessProto-OncogenesPublic HealthPublished CommentPumpQuality of lifeResearchResolutionSignal PathwaySpleenSuggestionSurfaceTestingTherapeuticTherapeutic EffectTissuesTreatment FailureTyrosine-Kinase OncogenesUnited States National Institutes of HealthVascular Endothelial Cellbasecell typechronic inflammatory diseasecomorbiditycoronary fibrosiscytokinedb/db mousedrug discoveryefficacy testingfundamental researchheart functionimprovedinnovationinterestmacrophagemolecular markermonocytemortalitypreservationprophylacticreceptorreduce symptomsresponsesubcutaneoussystemic inflammatory responsetranscriptome sequencingtreatment strategy
项目摘要
Abstract: Current heart failure (HF) treatments are not effective in heart failure with preserved ejection
fraction (HFpEF), despite the fact that 50% of all HF cases in the USA are HFpEF. Patients with HFpEF have
high incidences of mortality, hospitalizations, and a poor quality of life. Thus, there is a critical need to find
suitable therapeutic strategies for patients with HFpEF, based on pathophysiology. However, HFpEF
pathophysiology is complex due to systemic comorbidities like obesity, diabetes, and hypertension. Systemic
inflammation from such metabolic diseases a.k.a metabolic inflammation is key in driving the HFpEF
pathogenesis. Chronic inflammation occurs due to the imbalance between proinflammation and resolution,
including in HFpEF. Thus, we plan to develop suitable innovative therapies on strategies to improve the
resolution of inflammation to curtail HFpEF progression. Resolution is an orchestrated process carried out by
the actions of specialized pro-resolving mediators (SPMs) such as resolvins, lipoxins and maresins (secreted in
inflammatory exudates). SPMs bind to their specific receptors to elicit tissue homeostasis by reducing further
infiltration of leukocytes and increasing efferocytosis, i.e., clearing of cardiac apoptotic cells. Resolvin D1 (RvD1),
one of the potent SPMs, acts via its receptor, formyl-peptide receptor-2 (FPR2) and decreases pro-inflammatory,
pro-fibrotic gene expression and cytokines and promote efferocytosis. These effects are mediated via polarizing
blood/bone marrow derived monocytes and splenic/myocardial macrophages from proinflammatory to pro-
resolving phenotypes, that express FPR2. However, the effect of RVD1 in HFpEF, a big clinical issue with
unresolved inflammation, has not been studied. The primary goal of our R21 proposal is to test the efficacy of
RvD1 as a potential therapy for HFpEF driven by metabolic diseases. Thus, our proposal meets the goal of NIH’s
Special Interest (NOSI-ES-20-018) notice: Promoting Fundamental and Applied Research in Inflammation
Resolution. Mimicking all the features of human HFpEF in an animal model is challenging. However, db/db mice,
a model of obesity mediated T2DM, recapitulate the major features of HFpEF; hence, we chose to employ db/db
mice for the proposed studies. Our hypothesis is that RvD1 resolves systemic and cardiac inflammation by
reprogramming monocytes/macrophages and thereby ameliorating metabolic stress associated with HFpEF. We
propose two specific aims to test our hypothesis: 1) To determine the prophylactic effect of RvD1; and 2) To
determine the therapeutic effect of RvD1. We will treat the mice systemically with RvD1 before (for prophylactic
effects) and after (for therapeutic effects) onset of HFpEF. We will focus on RvD1 mediated increase in
efferocytosis of dying cardiac cells i.e., coronary vascular endothelial cells (aim 1) and cardiomyocytes (aim 2)
as its mechanism of action. The expected outcome of this project is to establish RvD1 as a therapeutic option
for HFpEF, a chronic inflammatory disease with no suitable treatments. Our innovative idea to target resolution
of metainflammation can move the drug discovery research for HFpEF forward.
摘要:目前的心力衰竭(HF)治疗方法对保留射血的心力衰竭无效
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Suresh Selvaraj Palaniyandi其他文献
Suresh Selvaraj Palaniyandi的其他文献
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{{ truncateString('Suresh Selvaraj Palaniyandi', 18)}}的其他基金
Resolvin D1 resolves inflammation in metabolic stress associated HFpEF
Resolvin D1 解决代谢应激相关 HFpEF 中的炎症
- 批准号:
10704156 - 财政年份:2022
- 资助金额:
$ 24.49万 - 项目类别:
4-hydroxy-2-nonenal in mitochondrial DNA damage and contractile dysfunction in diabetic heart: a role for aldehyde dehydrogenase 2
4-羟基-2-壬烯醛在糖尿病心脏线粒体 DNA 损伤和收缩功能障碍中的作用:乙醛脱氢酶 2 的作用
- 批准号:
9921470 - 财政年份:2018
- 资助金额:
$ 24.49万 - 项目类别:
4-hydroxy-2-nonenal in mitochondrial DNA damage and contractile dysfunction in diabetic heart: a role for aldehyde dehydrogenase 2
4-羟基-2-壬烯醛在糖尿病心脏线粒体 DNA 损伤和收缩功能障碍中的作用:乙醛脱氢酶 2 的作用
- 批准号:
9756477 - 财政年份:2018
- 资助金额:
$ 24.49万 - 项目类别:
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