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.
项目摘要
心血管疾病(CVD)与发达国家50%的死亡有关,因此是主要的疾病。
我们仍然远远没有治愈。除了心血管疾病的传统危险因素外,
肠道微生物代谢产物对心血管疾病发病机制的影响仅在
最近几次。三甲基胺-N-氧化物(TMAO),一种肠道微生物来源的膳食代谢产物
磷脂酰胆碱/肉毒碱在CVD患者的循环中升高,
动脉粥样硬化和心血管疾病的进展。目前的拨款建议试图定义
介导动脉内皮细胞(EC)对TMAO的反应的新分子信号传导机制,
这将为内皮功能障碍和血管损伤相关的发病机制提供新的见解。
动脉粥样硬化我们的初步结果表明,TMAO诱导的Nlrp 3炎性小体具有直接的
对内皮细胞的作用。因此,TMAO诱导炎性和非炎性作用,
内皮功能障碍最终导致动脉粥样硬化。这些代表了新的致病机制,
氧化三甲胺超过炎症。基于这些观察,我们假设肠道微生物代谢物,如
因为释放到循环中的TMAO充当内源性危险信号,
炎症和非炎症反应导致内皮功能障碍和血管损伤,
因此表现为动脉壁中的动脉粥样硬化形成。为了验证这一假设,我们将讨论如何
使用Nlrp 3-/-小鼠体内TMAO诱导内皮功能障碍和动脉粥样硬化,内皮特异性
Nlrp 3敲除小鼠(EC-Nlrp 3-/-)及其野生型同窝出生小鼠。然后我们将研究非炎症性
TMAO的作用导致内皮依赖性血管舒张、焦亡和DAMPs的产生,
体外和体内。最后,我们将探索新的分子信号通路介导TMAO诱导的
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
揭示了由微生物代谢物如TMAO诱导的CVD发病机制的新机制见解,
为开发临床相关的治疗动脉粥样硬化的新治疗策略铺平道路,
导致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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Sai Sudha Koka其他文献
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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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