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.
翻译后摘要:目前的心力衰竭(HF)的治疗是无效的心力衰竭保留射血
尽管事实上美国所有HF病例中有50%是HFpEF,但HFpEF仍存在。HFpEF患者有
高死亡率、住院率和低生活质量。因此,迫切需要找到
根据病理生理学,为HFpEF患者提供合适的治疗策略。然而,HFpEF
由于全身性合并症如肥胖症、糖尿病和高血压,病理生理学是复杂的。系统性
来自这类代谢性疾病的炎症,也就是代谢性炎症,是驱动HFpEF的关键
发病机制慢性炎症的发生是由于促炎症和消退之间的不平衡,
包括HFpEF。因此,我们计划开发合适的创新疗法,以改善
缓解炎症以缩短HFpEF进展。解决方案是一个精心策划的过程,
专门的促消退介质(SPM),如消退素,脂氧素和maresins(分泌在
炎性渗出物)。SPM与其特异性受体结合,通过进一步减少组织内分泌,
白细胞浸润和红细胞增多,即,清除心脏凋亡细胞。Resolvin D1(RvD1),
一种有效的SPM,通过其受体,甲酰肽受体-2(FPR 2)起作用,并减少促炎性,
促纤维化基因表达和细胞因子并促进红细胞增多。这些效应通过极化
血液/骨髓来源的单核细胞和脾/心肌巨噬细胞从促炎到促炎
解析表型,表达FPR 2。然而,RVD 1在HFpEF中的作用是一个很大的临床问题,
未解决的炎症,尚未研究。我们的R21提案的主要目标是测试
RvD 1作为代谢性疾病驱动的HFpEF的潜在疗法。因此,我们的建议符合NIH的目标,
特别关注(NOSI-ES-20-018)通知:促进炎症的基础和应用研究
分辨率在动物模型中模仿人类HFpEF的所有特征是具有挑战性的。然而,db/db小鼠,
肥胖介导的T2 DM模型,概括了HFpEF的主要特征;因此,我们选择使用db/db
小鼠进行拟议的研究。我们的假设是RvD 1通过以下途径解决全身和心脏炎症:
重编程单核细胞/巨噬细胞,从而改善与HFpEF相关的代谢应激。我们
提出两个具体目标来验证我们的假设:1)确定RvD 1的预防作用;和2)
确定RvD 1的治疗效果。我们将用RvD 1全身性治疗小鼠,然后(为了预防
效果)和HFpEF发作后(治疗效果)。我们将重点关注RvD 1介导的增加,
死亡心肌细胞的红细胞增多,即,冠状动脉血管内皮细胞(aim 1)和心肌细胞(aim 2)
作为其作用机制。该项目的预期结果是将RvD 1确立为一种治疗选择
HFpEF是一种慢性炎症性疾病,没有合适的治疗方法。我们的创新理念,
可以推动HFpEF的药物发现研究向前发展。
项目成果
期刊论文数量(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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