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
- 来源:
- 关键词:ATF6 geneAblationAccelerationAdultAdvanced Malignant NeoplasmAgingAntibodiesApcMin/+ miceApoptosis PromoterAtrophicAttenuatedBindingCachexiaCancer ModelCancer PatientCell Surface ReceptorsChronicChronic DiseaseComplicationDenervationDevelopmentDiseaseElderlyEndoplasmic ReticulumEukaryotic Initiation FactorsExerciseGene ExpressionGeneticHomeostasisIn VitroIndividualInduction of ApoptosisInflammationInflammatoryInositolKRASG12DKnockout MiceLinkMalignant NeoplasmsMediatingMediatorMembraneMetabolicMetabolic dysfunctionMitochondriaModelingMolecularMusMuscleMuscle FibersMuscle functionMuscular AtrophyNeuromuscular JunctionNutrientOrganellesOxidative StressPRKR genePathway interactionsPatientsPhosphotransferasesPopulationPreventionPrevention approachProkaryotic Initiation Factor-2Protein BiosynthesisProtein SecretionProteinsRNA SplicingRegulationReportingRepressionRoleSignal PathwaySignal TransductionSkeletal MuscleSkeletal Muscle NeoplasmStressSyndromeSystemTNF geneTherapeuticXBP1 geneactivating transcription factor 1agedarmcancer cachexiacell injurycytokineendoplasmic reticulum stressexperimental studyfrailtyimprovedin vivoknock-downmembermouse modelmuscle formnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpancreatic cancer modelpre-clinicalpreventprotein degradationprotein foldingreceptorresponsesarcopeniasensorskeletal muscle differentiationskeletal muscle growthskeletal muscle wastingtissue degenerationtumor
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
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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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
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
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$ 55.16万 - 项目类别:
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