Investigating the role of PHD3 in lipid homeostasis

研究 PHD3 在脂质稳态中的作用

基本信息

  • 批准号:
    10430260
  • 负责人:
  • 金额:
    $ 42.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary Adaptation of cellular metabolism is crucial for maintaining tissue and whole-body homeostasis. In response to low energy or stress, cells activate AMP-activated protein kinase (AMPK) to phosphorylate acetyl-CoA carboxylase (ACC), which increases mitochondrial fatty acid oxidation (FAO) and ATP levels. However, how FAO is downregulated in energy abundance states is not fully understood. As pathways that drive fuel addiction may provide new therapeutic targets or biomarkers for personalized therapy, there is a critical need to identify pathways that regulate metabolic homeostasis. We have discovered a new nutrient-dependent signaling pathway that controls fat oxidation via a little studied member of the prolyl hydroxylase domain protein family, PHD3. PHDs are a family of -ketoglutarate dependent dioxygenases that hydroxylate substrate proline residues and have been linked to fuel switching. We find that PHD3 regulates fatty acid metabolism by hydroxylating acetyl-CoA carboxylase (ACC2), a regulator of mitochondrial FAO. In response to nutrient abundance, PHD3 activates ACC2 to inhibit catabolism of fatty acids. Since ACC2 and PHD3 are highly expressed in oxidative tissues such as skeletal muscle, this proposal will test the hypothesis that the loss of PHD3 in skeletal muscle deregulates energy homeostasis by preventing ACC2 hydroxylation, hence causing constitutive mitochondrial oxidative metabolism. This proposal will test these ideas by: 1) defining the kinetics and determining the specificity by which PHD3-mediated hydroxylation regulates ACC2, 2) defining the role of PHD3 in nutrient signaling in skeletal muscle cell energetics, and 3) testing the physiological relevance of PHD3 in muscle energy homeostasis in vivo. First, we will utilize recombinant purified PHD3 to quantify the kinetic parameters of PHD3 hydroxylation of ACC2 versus HIF1. Next we will examine the specificity of ACC2 hydroxylation by PHD1-3 (Aim 1). We will also examine the effect of PHD3 on cellular metabolism in skeletal muscle cells in response to nutrient cues. We will examine the necessity of AMPK, ACC2, and HIF1 signaling on the metabolic roles of PHD3 (Aim 2). Finally, we will examine the consequences of PHD3 activity on skeletal muscle physiology in a resting state and during acute energy challenge (Aim 3). Our overarching goal is to elucidate the molecular elements of PHD3 signaling that control cellular metabolism and to leverage these findings to ultimately develop therapeutic strategies to promote improved muscle function and metabolic fitness.
项目总结

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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MARCIA HAIGIS其他文献

MARCIA HAIGIS的其他文献

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{{ truncateString('MARCIA HAIGIS', 18)}}的其他基金

Sirtuins and Cancer
Sirtuins 与癌症
  • 批准号:
    10646361
  • 财政年份:
    2022
  • 资助金额:
    $ 42.38万
  • 项目类别:
Investigating the role of PHD3 in lipid homeostasis
研究 PHD3 在脂质稳态中的作用
  • 批准号:
    10304448
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Investigating the role of PHD3 in lipid homeostasis
研究 PHD3 在脂质稳态中的作用
  • 批准号:
    10643900
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Profiling immune cells in aged lung tumor initiation
分析老年肺肿瘤发生过程中的免疫细胞
  • 批准号:
    10830688
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Progenitor cell states contributing to aging and lung cancer
祖细胞状态导致衰老和肺癌
  • 批准号:
    10494135
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Progenitor cell states contributing to aging and lung cancer
祖细胞状态导致衰老和肺癌
  • 批准号:
    10362891
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Progenitor cell states contributing to aging and lung cancer
祖细胞状态导致衰老和肺癌
  • 批准号:
    10693386
  • 财政年份:
    2021
  • 资助金额:
    $ 42.38万
  • 项目类别:
Frontiers of Aging: From Molecules to Physiology
衰老前沿:从分子到生理学
  • 批准号:
    9762278
  • 财政年份:
    2019
  • 资助金额:
    $ 42.38万
  • 项目类别:
Project 3: Mechanisms of immunotherapy action
项目3:免疫治疗作用机制
  • 批准号:
    10343841
  • 财政年份:
    2018
  • 资助金额:
    $ 42.38万
  • 项目类别:
Molecular mechanisms of Nutrient sensing in cancer
癌症营养感应的分子机制
  • 批准号:
    9494546
  • 财政年份:
    2017
  • 资助金额:
    $ 42.38万
  • 项目类别:

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