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

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

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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:
Branched chain amino acids and pancreatic cancer
支链氨基酸与胰腺癌
  • 批准号:
    10436144
  • 财政年份:
    2020
  • 资助金额:
    $ 74.24万
  • 项目类别:
Branched chain amino acids in heart failure
支链氨基酸在心力衰竭中的作用
  • 批准号:
    10371891
  • 财政年份:
    2020
  • 资助金额:
    $ 74.24万
  • 项目类别:
Branched chain amino acids in heart failure
支链氨基酸在心力衰竭中的作用
  • 批准号:
    9977599
  • 财政年份:
    2020
  • 资助金额:
    $ 74.24万
  • 项目类别:
Branched chain amino acids in heart failure
支链氨基酸在心力衰竭中的作用
  • 批准号:
    10599927
  • 财政年份:
    2020
  • 资助金额:
    $ 74.24万
  • 项目类别:
Branched chain amino acids and pancreatic cancer
支链氨基酸与胰腺癌
  • 批准号:
    10688001
  • 财政年份:
    2020
  • 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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The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
  • 批准号:
    8783415
  • 财政年份:
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  • 批准号:
    8996048
  • 财政年份:
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    $ 74.24万
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The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
  • 批准号:
    9125794
  • 财政年份:
    2014
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    $ 74.24万
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MODEL STUDIES OF ACETYL COENZYME A SYNTHASE
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    6727647
  • 财政年份:
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乙酰辅酶A合酶的模型研究
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    7046635
  • 财政年份:
    2000
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    2000
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  • 批准号:
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乙酰辅酶A合酶的模型研究
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MODEL STUDIES OF ACETYL COENZYME A SYNTHASE
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