TWEAK/Fn14/UPR Signaling in Skeletal Muscle Wasting

骨骼肌萎缩中的 TWEAK/Fn14/UPR 信号转导

基本信息

  • 批准号:
    10660397
  • 负责人:
  • 金额:
    $ 55.16万
  • 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 2028-01-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Skeletal muscle wasting/cachexia is a devastating complication of a number of chronic disease states, such as cancer and in the elderly population. Muscle wasting involves an imbalance in the rates of protein synthesis and degradation, functional denervation, metabolic abnormalities, and loss of mitochondrial content and function. TWEAK is a proinflammatory cytokine that binds to cell surface receptor Fn14 to activate multiple intracellular signaling pathways. We have found that the expression of Fn14 is increased in skeletal muscle of mouse models of cancer cachexia and in aged mice. Skeletal muscle-specific ablation of Fn14 inhibits muscle wasting in a murine model of cancer cachexia. TWEAK represses the rate of protein synthesis in skeletal muscle both in vivo and in vitro. Furthermore, the TWEAK-Fn14 system regulates ER stress- induced unfolded protein response (UPR) in skeletal muscle of tumor-bearing mice. In addition, our experiments demonstrate that targeted inhibition of the PERK and/or IRE1/XBP1 arms of the UPR improves protein synthesis in skeletal muscle of mice. However, the role of the TWEAK-Fn14 system and UPR pathways in the regulation of skeletal muscle mass and function during cancer cachexia and aging remains completely unknown. In this project, we will investigate the role of TWEAK/Fn14/UPR signaling axis in skeletal muscle atrophy and whether targeted genetic ablation of Fn14 or components of the UPR attenuate muscle wasting in preclinical mouse models of cancer cachexia and during aging. Based on our preliminary results, we hypothesize that the TWEAK/Fn14 system causes skeletal muscle wasting through the activation of the PERK and the IRE1α/XBP1 arms of the UPR during aging and cancer cachexia. Our specific aims are to: (I) Investigate the role of the TWEAK/Fn14 system in skeletal muscle wasting during aging and cancer cachexia, and (II) Investigate the mechanisms by which TWEAK/Fn14-induced activation of the UPR pathways cause skeletal muscle wasting during aging and cancer cachexia. Our proposed studies will identify key mechanisms responsible for the loss of skeletal muscle mass. Successful completion of this project will provide strong basis for the development of new therapies for sarcopenia and cancer cachexia.
摘要

项目成果

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ASHOK KUMAR其他文献

ASHOK KUMAR的其他文献

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{{ truncateString('ASHOK KUMAR', 18)}}的其他基金

TAK1 signaling in skeletal muscle
骨骼肌中的 TAK1 信号传导
  • 批准号:
    10201515
  • 财政年份:
    2019
  • 资助金额:
    $ 55.16万
  • 项目类别:
TAK1 signaling in skeletal muscle
骨骼肌中的 TAK1 信号传导
  • 批准号:
    10005646
  • 财政年份:
    2019
  • 资助金额:
    $ 55.16万
  • 项目类别:
Non-Coding Variants of Angiotensinogen Gene and Hypertension
血管紧张素原基因的非编码变异与高血压
  • 批准号:
    9197334
  • 财政年份:
    2016
  • 资助金额:
    $ 55.16万
  • 项目类别:
Non-Coding Variants of Angiotensinogen Gene and Hypertension
血管紧张素原基因的非编码变异与高血压
  • 批准号:
    9325162
  • 财政年份:
    2016
  • 资助金额:
    $ 55.16万
  • 项目类别:
MYD88 Signaling in Mammalian Myoblast Fusion
哺乳动物成肌细胞融合中的 MYD88 信号转导
  • 批准号:
    9336240
  • 财政年份:
    2015
  • 资助金额:
    $ 55.16万
  • 项目类别:
MYD88 Signaling in Mammalian Myoblast Fusion
哺乳动物成肌细胞融合中的 MYD88 信号转导
  • 批准号:
    9144184
  • 财政年份:
    2015
  • 资助金额:
    $ 55.16万
  • 项目类别:
Aldosterone Synthase & Hypertension
醛固酮合酶
  • 批准号:
    9052214
  • 财政年份:
    2014
  • 资助金额:
    $ 55.16万
  • 项目类别:
Aldosterone Synthase and Hypertension
醛固酮合酶与高血压
  • 批准号:
    8673375
  • 财政年份:
    2014
  • 资助金额:
    $ 55.16万
  • 项目类别:
Aldosterone Synthase & Hypertension
醛固酮合酶
  • 批准号:
    8837685
  • 财政年份:
    2014
  • 资助金额:
    $ 55.16万
  • 项目类别:
TAK1/TRAF6 Signaling in Skeletal Muscle
骨骼肌中的 TAK1/TRAF6 信号传导
  • 批准号:
    8502172
  • 财政年份:
    2011
  • 资助金额:
    $ 55.16万
  • 项目类别:

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