Metabolic control in vascular remodeling

血管重塑中的代谢控制

基本信息

  • 批准号:
    10543542
  • 负责人:
  • 金额:
    $ 59.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-03-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Summary Vascular remodeling is essential for artery formation during embryogenesis and in the pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant- associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete understanding of the process of vascular remodeling limits current abilities to develop preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of developmental and adult vascular remodeling, but mechanisms underlying SMC activities are not fully elucidated — in particular, the role of mitochondria and metabolism in this context is relatively unexplored. The goal of this proposal is to understand mitochondrion-based mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured SMCs decreases complex I levels and activity, limits the formation of supercomplexes containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly expressed during mouse development in SMCs building the arterial wall, and in adult mice in SMC-derived cells that form the expanding neointima that accumulates in response to arterial injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells require respiratory complex I for normal embryogenesis. We hypothesize that complex I promotes SMC activities important for vascular remodeling during embryogenesis and in adulthood. We will test this hypothesis in three specific aims that respectively address the effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse vascular development, and 3) in models of adult vascular homeostasis, injury, and atherosclerotic disease. These studies will add a new respiratory complex-based angle — susceptible to pharmacological intervention — to our understanding of how arteries form and how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis, tumor vascularization, and vascular disease.
总结

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neutrophil extracellular traps in cardiac hypertrophy: a KLF2 perspective.
The FAT1 Cadherin Drives Vascular Smooth Muscle Cell Migration.
  • DOI:
    10.3390/cells12121621
  • 发表时间:
    2023-06-14
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Riascos-Bernal, Dario F.;Ressa, Gaia;Korrapati, Anish;Sibinga, Nicholas E. S.
  • 通讯作者:
    Sibinga, Nicholas E. S.
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Nicholas E Sibinga其他文献

Nicholas E Sibinga的其他文献

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{{ truncateString('Nicholas E Sibinga', 18)}}的其他基金

Allograft inflammatory factor-1 and immune tolerance
同种异体移植物炎症因子-1和免疫耐受
  • 批准号:
    10511362
  • 财政年份:
    2022
  • 资助金额:
    $ 59.36万
  • 项目类别:
FAT cadherins and vascular remodeling
FAT 钙粘蛋白和血管重塑
  • 批准号:
    10586704
  • 财政年份:
    2022
  • 资助金额:
    $ 59.36万
  • 项目类别:
Allograft inflammatory factor-1 and immune tolerance
同种异体移植物炎症因子-1和免疫耐受
  • 批准号:
    10642960
  • 财政年份:
    2022
  • 资助金额:
    $ 59.36万
  • 项目类别:
Metabolic control in vascular remodeling
血管重塑中的代谢控制
  • 批准号:
    10330406
  • 财政年份:
    2020
  • 资助金额:
    $ 59.36万
  • 项目类别:
Beta-catenin in vascular homeostasis and remodeling
β-连环蛋白在血管稳态和重塑中的作用
  • 批准号:
    9507901
  • 财政年份:
    2017
  • 资助金额:
    $ 59.36万
  • 项目类别:
Beta-catenin in vascular homeostasis and remodeling
β-连环蛋白在血管稳态和重塑中的作用
  • 批准号:
    9884555
  • 财政年份:
    2017
  • 资助金额:
    $ 59.36万
  • 项目类别:
Colony stimulating factor-1 in graft vascular disease
移植血管疾病中的集落刺激因子-1
  • 批准号:
    9276113
  • 财政年份:
    2015
  • 资助金额:
    $ 59.36万
  • 项目类别:
Allograft inflammatory factor-1 in atherosclerosis
同种异体移植物炎症因子-1在动脉粥样硬化中的作用
  • 批准号:
    8913555
  • 财政年份:
    2015
  • 资助金额:
    $ 59.36万
  • 项目类别:
Colony stimulating factor-1 in graft vascular disease
移植血管疾病中的集落刺激因子-1
  • 批准号:
    8985741
  • 财政年份:
    2015
  • 资助金额:
    $ 59.36万
  • 项目类别:
The Fat1 Cadherin in Atherosclerotic Vascular Disease
Fat1 钙粘蛋白在动脉粥样硬化性血管疾病中的作用
  • 批准号:
    8109076
  • 财政年份:
    2011
  • 资助金额:
    $ 59.36万
  • 项目类别:

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