Acetate and Endothelial Pathobiology
醋酸盐和内皮病理学
基本信息
- 批准号:10736268
- 负责人:
- 金额:$ 74.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcetatesAcetyl Coenzyme AAcetylationAnimal ModelArterial DisorderArterial Fatty StreakAtherosclerosisBlood VesselsBypassCellular Metabolic ProcessChronicCitratesCytoplasmDataDevelopmentDiseaseEndothelial CellsEndotheliumEnzymesEventFeedbackGenerationsGenetically Engineered MouseGlucoseGoalsHypoxiaIn VitroInflammationLinkMass Spectrum AnalysisMesenchymalMetabolicMetabolic ActivationMetabolic ControlMetabolic PathwayMetabolismMitochondriaMusMyocardial InfarctionOralPaintPathologyPathway interactionsPeripheral Vascular DiseasesPhosphorylationPhysiologicalPlayPreventionProcessProductionProtein AcetylationPulmonary HypertensionPyruvatePyruvate Dehydrogenase ComplexRNA InterferenceRegulationRoleSignal TransductionSiteSmooth Muscle MyocytesSourceStrokeTechniquesTestingTherapeuticTherapeutic AgentsTransforming Growth Factor betaTranslatingTransplantationanaerobic glycolysisclinical practicedefined contributiondriving forceefficacy testingin vitro testingin vivoin vivo evaluationinhibitormouse modelnanoparticlenanoparticle deliverynovelnovel therapeutic interventionnovel therapeuticspreventpulmonary arterial hypertensionpyruvate dehydrogenaseside effectsuccesstargeted treatmenttherapeutic evaluationtherapeutic targettherapeutically effectivetranslational approachvascular inflammation
项目摘要
Chronic vascular inflammation is a hallmark of atherosclerosis, pulmonary arterial
hypertension (PAH) and related conditions. It is also one of the principal causes of endothelial-
to-mesenchymal transition (EndMT). We have recently demonstrated that disruption of EndMT,
achieved by inhibiting endothelial-specific TGFβ signaling input, results in extensive (~70%)
regression of established atherosclerotic lesion and prevention of development of new ones. It
also prevents development of hypoxia-induced PAH. These data suggest that EndMT is key to
the development and progression of illnesses associated with chronic inflammation, such as
atherosclerosis, PAH, and transplant arteriopathy.
However, a therapeutic strategy that relies on suppressing EndMT via control of endothelial
TGFβ signaling is complicated because of the need of endothelial-specific delivery of
therapeutic agents (systemic inhibition of TGFβ signaling is fraught with side effects and has
been shown to promote atherosclerosis via its effects on smooth muscle cells). For these
reasons, we focused on identifying another EndMT control point that can serve as an effective
therapeutic target. Since endothelial cells have unique metabolic requirements and pathways,
we concentrated on identifying potential metabolic-related control of EndMT.
Our preliminary studies indicate that there indeed is metabolic control of EndMT that
operates via acetylation-dependent regulation of TGFβ signaling. Moreover, the Ac-CoA needed
for these acetylation events appears to be in large part derived atypically from acetate. Our goal
in this application is to rigorously define and characterize the unique endothelial metabolic
pathway that leads to generation of cytoplasmic Ac-CoA from acetate and the role that this Ac-
CoA plays in TGFβ signaling. This will be tested in vitro and in vivo using genetically engineered
mice. Finally, we will test two distinct translational strategies – a nanoparticle-based EC-specific
RNAi delivery, and an oral specific inhibitor to test the effect of suppression of acetate-based
Ac-CoA production on the development and progression of atherosclerosis
慢性血管炎症是动脉粥样硬化的标志
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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Zoltan P Arany其他文献
Zoltan P Arany的其他文献
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{{ truncateString('Zoltan P Arany', 18)}}的其他基金
Comprehensive quantification of fuel use in cold-induced thermogenesis in vivo
体内冷诱导生热过程中燃料使用的综合量化
- 批准号:
10637680 - 财政年份:2023
- 资助金额:
$ 74.24万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10343859 - 财政年份:2021
- 资助金额:
$ 74.24万 - 项目类别:
High-throughput screening for modulators of vascular fat transport to treat and prevent diabetes
高通量筛选血管脂肪转运调节剂以治疗和预防糖尿病
- 批准号:
10331230 - 财政年份:2021
- 资助金额:
$ 74.24万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino Acids
保持肌肉中的脂肪——支链氨基酸的作用
- 批准号:
10186735 - 财政年份:2018
- 资助金额:
$ 74.24万 - 项目类别:
Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance
保持肌肉中的脂肪 - 支链氨基酸氨基酸在胰岛素抵抗中的作用
- 批准号:
10736605 - 财政年份:2018
- 资助金额:
$ 74.24万 - 项目类别:
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