Coordination of PAR and Ub signaling in mitochondria

线粒体中 PAR 和 Ub 信号传导的协调

基本信息

  • 批准号:
    10623889
  • 负责人:
  • 金额:
    $ 43.14万
  • 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:
    2023-04-01 至 2028-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Over the past 10 years, our research program has aimed at discovering molecular mechanisms that control metabolic adaptation in response to nutrient availability, cellular differentiation, and oxidative stress through genomic reprogramming. With NIGMS support, we have made significant contributions to identifying mechanisms responsible for the coordinated regulation of gene transcription and translation during the Mitochondrial Stress Response (MSR). Our work has identified a key role for non-degradative ubiquitination in both processes, showing that the regulated shuttling of GPS2 – an endogenous inhibitor of K63 ubiquitination – between mitochondria and nucleus is an essential strategy for maintaining mitochondrial homeostasis. As a complement to these mechanistic studies, we also investigated – in projects supported by NIDDK and the Department of Defense – the physiological relevance and translational potential GPS2-mediated regulation of ubiquitin signaling in breast cancer and obesity-associated disorders. Together, these studies have revealed the importance of GPS2-mediated restriction of K63Ub signaling in promoting metabolic adaptation and mitochondria remodeling during stress and cellular differentiation. This large body of work highlights our expertise in the field and our unique position to further investigate the crosstalk between this newly identified pathway and other PTMs involved in regulating mitochondrial function. In particular, we will focus our future studies on the crosstalk between ubiquitination and ADP-ribosylation. These PTMs work in tandem in the regulation of nuclear genome stability, innate immunity and stress-induced translational regulation. However, their relationship in regulating mitochondrial function has not yet been investigated. In fact, although the presence of ADP-ribosylation activity in mitochondria was known for decades, the identity of the mitochondrial ART enzyme/s has been elusive, hindering more detailed studies on the role and regulation of mitochondrial proteins through ADP-ribosylation. As we recently identified NEURL4 as a mitochondria-dedicated ADP-ribosyl transferase under the regulation of stress-induced and GPS2-mediated reprogramming, we are now in the position of carrying those studies. We propose a research plan spanning two major areas:1) Investigating the spatial and functional regulation of mitochondria retrograde signaling in response to mitochondrial stress and 2) Exploring the crosstalk between ubiquitination and ADP-ribosylation in regulating mitochondrial homeostasis. Our research plan addresses three key problems: i) the spatial regulation of mitochondria retrograde signaling; ii) the functional contribution of mitochondria retrograde signaling to the regulation of ADP-ribosylation and ubiquitination across subcellular compartments; iii) the molecular mechanisms underlying the coordinated regulation of ADP-ribosylation/ ubiquitination. Successful completion of the proposed studies will lead to a better understanding of the mechanisms regulating mitochondria homeostasis through post-translational modifications and possibly reveal regulatory strategies to be targeted for therapeutic purposes.
项目总结/文摘

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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VALENTINA PERISSI其他文献

VALENTINA PERISSI的其他文献

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{{ truncateString('VALENTINA PERISSI', 18)}}的其他基金

Regulation of mitochondrial homeostasis through retrograde signaling
通过逆行信号调节线粒体稳态
  • 批准号:
    9924614
  • 财政年份:
    2018
  • 资助金额:
    $ 43.14万
  • 项目类别:
Regulation of mitochondrial homeostasis through retrograde signaling
通过逆行信号调节线粒体稳态
  • 批准号:
    10133090
  • 财政年份:
    2018
  • 资助金额:
    $ 43.14万
  • 项目类别:
Ubiquitin-dependent regulation of inflammation and insulin resistance
炎症和胰岛素抵抗的泛素依赖性调节
  • 批准号:
    9243244
  • 财政年份:
    2014
  • 资助金额:
    $ 43.14万
  • 项目类别:
Ubiquitin-dependent regulation of inflammation and insulin resistance
炎症和胰岛素抵抗的泛素依赖性调节
  • 批准号:
    9040938
  • 财政年份:
    2014
  • 资助金额:
    $ 43.14万
  • 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
  • 批准号:
    8328959
  • 财政年份:
    2010
  • 资助金额:
    $ 43.14万
  • 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
  • 批准号:
    8149970
  • 财政年份:
    2010
  • 资助金额:
    $ 43.14万
  • 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
  • 批准号:
    8138837
  • 财政年份:
    2010
  • 资助金额:
    $ 43.14万
  • 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
  • 批准号:
    7300065
  • 财政年份:
    2007
  • 资助金额:
    $ 43.14万
  • 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
  • 批准号:
    7456334
  • 财政年份:
    2007
  • 资助金额:
    $ 43.14万
  • 项目类别:

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