Dual Functionality of Ceramide in Human Microvascular Endothelial Function
神经酰胺在人体微血管内皮功能中的双重功能
基本信息
- 批准号:10636908
- 负责人:
- 金额:$ 63.24万
- 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:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdipose tissueAntiinflammatory EffectArteriesAtherosclerosisBlood VesselsCardiacCardiovascular DiseasesCeramidesChronicComplementCoronaryCoronary ArteriosclerosisDataDevelopmentDilatorDiseaseEFRACEndotheliumEventExposure toFatty acid glycerol estersGenerationsGoalsHealthHeart failureHumanHydrogen PeroxideIndividualKnowledgeMediatingMediatorMetabolismMicrocirculationMicrovascular DysfunctionMitochondriaNADPH OxidaseNOS3 geneNitric OxidePathogenicityPathologicPathway interactionsPatientsPerfusionPeripheralPhenotypePlasmaPlayProductionResearchRiskRisk FactorsRoleSignal TransductionSphingolipidsSphingosine-1-Phosphate ReceptorStressTherapeutic InterventionTissuesVascular Endotheliumacute stressarteriolecaveolin 1endothelial dysfunctionin vivoinflammatory milieunew therapeutic targetnovelnovel strategiespreservationpressurepreventresponseshear stresssphingosine 1-phosphatetargeted treatmenttheoriestranslational approachtranslational studyvascular endothelial dysfunctionvolunteer
项目摘要
Project Summary
Elevated levels of plasma ceramide are an independent risk factor for major adverse cardiac events (MACE)
and are associated with cardiovascular diseases including coronary artery disease (CAD) and heart failure with
preserved ejection fraction (HFpEF). Endothelial microvascular dysfunction, the loss of nitric oxide (NO)-
mediated dilation to flow (flow-induced dilation; FID), precedes the development of CAD and occurs following
chronic exposure to exogenous ceramide. During disease, following acute stress (e.g. high pressure), or after
chronic ceramide treatment, FID is maintained by utilizing mitochondrial-derived hydrogen peroxide (H2O2).
Although effective at eliciting dilation, unlike the anti-inflammatory effects of NO, H2O2 promotes an inflammatory
environment within the vasculature and surrounding parenchymal tissue. The mechanism(s) by which ceramide
promotes mitochondrial H2O2-mediated FID remains unknown. Interestingly, ceramide has also been implicated
as a critical signaling component in the generation of NO. The ceramide metabolite sphingosine-1-phosphate
(S1P) exerts opposing effects on the endothelium, promotes the formation of NO, and may explain the positive
vascular effects associated with ceramide. A large knowledge gap exists regarding the dual functionality of
ceramide within the human microvascular endothelium. We hypothesize that while ceramide formation is a
critical mechanistic component in NO-mediated FID, prolonged exposure initiates a signaling cascade that
results in the release of mitochondrial H2O2 in response to shear. Our aims are as follows; 1) determine the
necessary role of ceramide in maintaining NO-mediated FID within the human microcirculation, and 2)
investigate the mechanism(s) by which ceramide formation during stress or disease initiates the transition in FID
mediator from NO to mitochondrial-derived H2O2. Using a novel approach, these mechanistic studies will be
complemented by the first human in vivo study to examine the effect of elevated plasma ceramide on peripheral
microvascular function. The translational studies proposed in this application will enhance our understanding of
ceramide signaling during health, disease, and following acute stress. This information will provide new targets
for therapeutic intervention in individuals at risk for developing cardiovascular disease including CAD and
HFpEF.
项目摘要
血浆神经酰胺水平升高是主要不良心脏事件(MACE)的独立风险因素
并与心血管疾病(包括冠状动脉疾病(CAD)和心力衰竭)相关,
射血分数保留(HFpEF)。内皮微血管功能障碍,一氧化氮(NO)的损失-
血流介导的扩张(血流诱导的扩张; FID),先于CAD的发展,发生于
长期暴露于外源性神经酰胺患病期间、急性应激(如高压)后或
在慢性神经酰胺治疗中,通过利用尿道衍生的过氧化氢(H2 O2)来维持FID。
尽管H2 O2在引起扩张方面是有效的,但与NO的抗炎作用不同,H2 O2促进了炎性扩张。
在脉管系统和周围实质组织内的环境中。神经酰胺的作用机制
促进线粒体H2 O2介导的FID仍然未知。有趣的是,神经酰胺也与
神经酰胺代谢物鞘氨醇-1-磷酸是NO产生的关键信号成分
(S1P)对内皮细胞产生相反的作用,促进NO的形成,并可能解释阳性反应。
与神经酰胺相关的血管效应。在以下两个方面存在着巨大的知识差距:
人微血管内皮细胞内的神经酰胺。我们假设,虽然神经酰胺的形成是一个
作为NO介导的FID的关键机制成分,长时间暴露会引发信号级联反应,
导致线粒体H2 O2响应剪切而释放。我们的目标如下:1)确定
神经酰胺在维持人体微循环内NO介导的FID中的必要作用,以及2)
研究应激或疾病期间神经酰胺形成引发FID转变的机制
介体从NO到衍生自水的H2 O2。使用一种新的方法,这些机制的研究将是
补充的是第一个人体体内研究,以检查血浆神经酰胺升高对外周血的影响。
微血管功能本申请中提出的翻译研究将增强我们对
神经酰胺信号在健康,疾病和急性应激后。这些信息将提供新的目标
用于有发生心血管疾病(包括CAD)风险的个体的治疗性干预,
HFpEF。
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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{{ truncateString('Julie K Freed', 18)}}的其他基金
Specialized Training in Anesthesiology Team Science
麻醉学团队科学专业培训
- 批准号:
10555365 - 财政年份:2023
- 资助金额:
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Estrogen as a Regulator of the Sphingolipid Balance in the Human Microcirculation
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- 批准号:
10556913 - 财政年份:2022
- 资助金额:
$ 63.24万 - 项目类别:
Dual Functionality of Ceramide in Human Microvascular Endothelial Function
神经酰胺在人体微血管内皮功能中的双重功能
- 批准号:
10517742 - 财政年份:2022
- 资助金额:
$ 63.24万 - 项目类别:
NOVEL ROLE OF SPHINGOLIPIDS IN MAINTAINING VASCULAR HOMEOSTASIS
鞘脂在维持血管稳态方面的新作用
- 批准号:
10314025 - 财政年份:2018
- 资助金额:
$ 63.24万 - 项目类别:
NOVEL ROLE OF SPHINGOLIPIDS IN MAINTAINING VASCULAR HOMEOSTASIS
鞘脂在维持血管稳态方面的新作用
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10063902 - 财政年份:2018
- 资助金额:
$ 63.24万 - 项目类别:
NOVEL ROLE OF SPHINGOLIPIDS IN MAINTAINING VASCULAR HOMEOSTASIS
鞘脂在维持血管稳态方面的新作用
- 批准号:
10531555 - 财政年份:2018
- 资助金额:
$ 63.24万 - 项目类别:
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