Role of Trimethylamine-N-oxide in endothelial dysfunction
三甲胺-N-氧化物在内皮功能障碍中的作用
基本信息
- 批准号:10446776
- 负责人:
- 金额:$ 38.75万
- 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:2022-08-19 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAddressAdhesionsApplications GrantsArterial Fatty StreakArteriesAtherosclerosisBlood CirculationBlood VesselsCASP1 geneCardiovascular DiseasesCardiovascular systemCarnitineCarotid ArteriesCaspase InhibitorCathepsins BCellsCeramidesCessation of lifeCholineDeveloped CountriesDiseaseDisease ProgressionEndothelial CellsEndotheliumExposure toFluorochromeHMGB1 geneHealthHeartHigh Mobility Group ProteinsHomingHumanImpairmentIn VitroInflammasomeInflammationInflammatoryInflammatory ResponseInterleukin-1Interleukin-18IntestinesKnockout MiceKnowledgeLeadLecithinLysosomesMediatingMembraneMetabolicMolecularMorbidity - disease rateMultivesicular BodyMusNADPH OxidaseNitric OxideNucleotidesPathogenesisPathogenicityPatientsPatternPermeabilityPlasmaProcessProductionProteinsRisk FactorsRodentRodent ModelRoleSclerosisSeriesSignal PathwaySignal TransductionSphingolipidsSphingosineSuperoxidesT-LymphocyteTestingTight JunctionsTimeTransmission Electron MicroscopyVasodilationWorkacid sphingomyelinaseatherogenesisbasecardiovascular injurycardiovascular risk factorcell injuryclinical developmentclinically relevantdietaryendothelial dysfunctionendothelial regenerationendothelial stem cellexosomegut microbesin vivoinnovationinsightmacrophagemarenostrinmetabolomicsmicrobialmonocytemortalitynew therapeutic targetnovelnovel therapeutic interventionreceptorrecruitrepairedresponsesphingosine 1-phosphatetraffickingtrimethyloxaminevascular inflammationvascular injury
项目摘要
Project Summary
Cardiovascular diseases (CVDs) are implicated in 50% of deaths in developed countries and is thus a major
health concern and we still remain far from a cure. In addition to the traditional risk factors for CVDs, the
influence exerted by gut microbial metabolites on the pathogenesis of CVDs has been recognized only in
recent times. Trimethylamine-N-oxide (TMAO), a gut microbe-derived metabolite of dietary
phosphatidylcholine/carnitine is elevated in the circulation of CVD patients and has been associated with
atherosclerosis and CVD progression in rodents and humans. The present grant proposal attempts to define
novel molecular signaling mechanisms mediating the responses of arterial endothelial cells (ECs) to TMAO,
which will provide new insights into the pathogenesis of endothelial dysfunction and vascular injury associated
with atherosclerosis. Our preliminary results have shown that TMAO induced Nlrp3 inflammasomes have direct
actions on the endothelial cells. Thus TMAO induces both inflammatory and non-inflammatory effects leading
to endothelial dysfunction and ultimately atherosclerosis. These represents novel pathogenic mechanisms of
TMAO beyond inflammation. Based on these observations, we hypothesize that gut microbial metabolites such
as TMAO which are released into the circulation act as endogenous danger signals and induce both
inflammatory and non-inflammatory responses leading to endothelial dysfunction and vascular injury which
consequently manifests into atherogenesis in the arterial wall. To test this hypothesis, we will address how
TMAO induces endothelial dysfunction and atherosclerosis in in vivo using Nlrp3-/- mice, endothelium-specific
Nlrp3 knockout mice (EC-Nlrp3-/-) and their wild type littermates. We will then investigate the non-inflammatory
effects of TMAO leading to endothelium dependent vasodilation, pyroptosis and DAMPs production both in
vitro and in vivo. Lastly, we will explore the novel molecular signaling pathways mediating TMAO-induced
endothelial exosome release leading to endothelial dysfunction and vascular injury. The proposed studies will
reveal new mechanistic insights of CVD pathogenesis induced by microbial metabolites such as TMAO and will
pave way to the development of clinically relevant, novel therapeutic strategies for treating atherosclerosis and
resulting CVDs.
项目概要
发达国家 50% 的死亡与心血管疾病 (CVD) 有关,因此是一个主要的疾病
健康问题,我们仍然距离治愈还很远。除了心血管疾病的传统危险因素外,
肠道微生物代谢物对 CVD 发病机制的影响仅在
最近几次。三甲胺-N-氧化物 (TMAO),一种肠道微生物衍生的饮食代谢物
CVD 患者的循环中磷脂酰胆碱/肉碱升高,并与
啮齿动物和人类的动脉粥样硬化和心血管疾病进展。本赠款提案试图定义
介导动脉内皮细胞 (EC) 对 TMAO 反应的新型分子信号传导机制,
这将为内皮功能障碍和相关血管损伤的发病机制提供新的见解
患有动脉粥样硬化。我们的初步结果表明TMAO诱导的Nlrp3炎症小体具有直接作用
对内皮细胞的作用。因此,TMAO 会诱导炎症和非炎症作用,从而导致
导致内皮功能障碍并最终导致动脉粥样硬化。这些代表了新的致病机制
TMAO 超越炎症。基于这些观察,我们假设肠道微生物代谢物如
因为 TMAO 被释放到循环中,充当内源性危险信号,并诱发
炎症和非炎症反应导致内皮功能障碍和血管损伤
因此表现为动脉壁动脉粥样硬化。为了检验这个假设,我们将讨论如何
TMAO 在 Nlrp3-/- 小鼠体内诱导内皮功能障碍和动脉粥样硬化,内皮特异性
Nlrp3 敲除小鼠 (EC-Nlrp3-/-) 及其野生型同窝小鼠。然后我们将调查非炎症
TMAO 导致内皮依赖性血管舒张、细胞焦亡和 DAMP 产生的影响
体外和体内。最后,我们将探索介导TMAO诱导的新型分子信号通路
内皮外泌体释放导致内皮功能障碍和血管损伤。拟议的研究将
揭示TMAO等微生物代谢物诱导的CVD发病机制的新机制
为治疗动脉粥样硬化和临床相关的新型治疗策略的开发铺平道路
由此产生的CVD。
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('Sai Sudha Koka', 18)}}的其他基金
Role of Trimethylamine-N-oxide in endothelial dysfunction
三甲胺-N-氧化物在内皮功能障碍中的作用
- 批准号:
10888738 - 财政年份:2022
- 资助金额:
$ 38.75万 - 项目类别:
Gut microbial metabolite- Trimethylamine-N-oxide and endothelial inflammasome signaling in cardiovascular injury
肠道微生物代谢物-三甲胺-N-氧化物和心血管损伤中的内皮炎性体信号传导
- 批准号:
10002639 - 财政年份:2019
- 资助金额:
$ 38.75万 - 项目类别:
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