Identifying mechanisms of deregulated mTORC1 activity during skeletal muscle atrophy
Identifying mechanisms of deregulated mTORC1 activity during skeletal muscle atrophy
批准号:
9180206
负责人:
William Comb
金额:
$9.44万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2017-03-03
关键词:
AchievementAgeAgingAnabolismAnimal ModelAnimalsAtrophicAutophagocytosisAwardBed restBiochemicalBiochemical GeneticsBiomedical ResearchCatabolismCell modelCellsComplexCultured CellsDefectDiseaseElderlyEpitopesEventExerciseFRAP1 geneFastingGenesGenetic screening methodGrowthHealthHumanHypertrophyIn SituIn VitroIndividualKnock-inKnock-in MouseKnowledgeLifeLysosomesMass Spectrum AnalysisMechanical StressMechanicsMediatingMediator of activation proteinMembrane PotentialsMentorsModelingMolecularMouse StrainsMusMuscleMuscle FibersMuscle functionMuscular AtrophyNeuronsNutrientNutritionalPathway interactionsPhasePlayPopulationPreventionProteomicsRaptorsRegulationResearch PersonnelResistanceRoleSarcomeresSignal PathwaySignal TransductionSkeletal MuscleStimulusSurfaceSystemTestingTissuesTraumatic injuryTuberous sclerosis protein complexabstractingage-related muscle lossagedbasecareercell growthcombatcomparativeexperiencefrailtygenetic regulatory proteinin vitro Modelin vivolive cell imagingmTOR inhibitionmuscle agingmuscle formmuscle hypertrophynovelnovel strategiesprogramsresponsesarcopeniaskeletal muscle wastingtoolwasting
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Skeletal muscle wasting (atrophy) results from a number of pathological insults and poses a serious
threat to human health. The mTOR Complex 1 (mTORC1) signaling pathway is a major regulator of cell growth,
activated in response to nutrients and exercise to promote accretion of skeletal muscle mass. During atrophy,
mTORC1 activity is inhibited which is significant because it reflects a shift of this tissue from anabolism
(growth) to catabolism (wasting). Interestingly, atrophy occurring from muscle disuse results in an inability of
nutrients to stimulate mTORC1 activity and cellular anabolism (anabolic resistance). This observation suggests
a complex interplay between mechanical and nutritional skeletal muscle inputs, though a molecular basis for
this relationship has not been resolved. Modeling muscle disuse and anabolic resistance in vitro is not a trivial
task; a molecular understanding of mTORC1 regulation in skeletal muscle has not been realized due to
experimental limitations of current cellular models. I have developed robust in vitro systems and animal models
that will enable the cellular, biochemical, and genetic strategies necessary to uncover mechanisms of crosstalk
between mechanical and nutrient inputs to mTORC1 in skeletal muscle. During the mentored phase of this
award (K99), I will use these tools to 1) gain an understanding of how mechanical stress (cellular tension) and
neuronal input (membrane potential) influence canonical mTORC1 signaling; 2) identify molecular-mediators of
mechanical and nutritional crosstalk; and 3) identify biochemically how mTORC1 regulatory complexes are
remodeled during states of atrophy. These studies will provide a mechanistic basis for mTORC1 inhibition
during skeletal muscle atrophy and reveal strategies to combat loss of muscle mass during disuse. As an
independent investigator (R00) I will apply the cellular systems, animal models, and knowledge generated
during the mentored phase to investigate an equally important question of how mTORC1 activity is disrupted in
aged muscle and contributes to sarcopenia (progressive loss of muscle mass with aging). Sarcopenia
represents a significant threat to our elderly population as it underlies traumatic injuries resulting from frailty.
This question reflects a logical scientific progression since many hallmarks of disuse-associated atrophy are
shared with aging-associated atrophy, but it is unknown if the molecular mechanisms promoting loss of muscle
mass are the same in these two states. With the strategies developed in this proposal, I will 1) determine if
mechanical stress influences mTORC1 activity in aged muscle, 2) identify biochemical alterations in mTORC1
regulatory proteins in aged muscle, and 3) understand physiologically, how novel mTORC1 regulatory proteins
contribute to sarcopenia. Achievement of the aims outlined in this proposal will represent a significant
advancement in our understanding of signaling defects that underlie muscle atrophy and provide a wealth of
scientific questions to pursue as I establish an independent career in biomedical research.
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批准号:8525561
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项目类别:
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资助金额:$1.42万
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财政年份:2013
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负责人:William Comb
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依托单位:
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