Investigating the Molecular Mechanisms of Skeletal Muscle Atrophy
研究骨骼肌萎缩的分子机制
基本信息
- 批准号:8762223
- 负责人:
- 金额:$ 1.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-11-01 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAgingAtrophicBed restCell NucleusCell modelChronicChronic Obstructive Airway DiseaseComplexCultured CellsDNADNA Modification MethylasesDataDiseaseEnzymesEventFamilyFastingFractureGADD45A geneGenesGoalsHealthHeart failureHospitalizationHumanIndependent LivingIndividualInsulin ResistanceInvestigationLeadLimb structureMalignant NeoplasmsMammalian CellMediatingMedicineMessenger RNAMethylationModelingMolecularMusMuscleMuscle FibersMuscular AtrophyNuclear ProteinNucleotide Excision RepairPathogenesisPathway interactionsPatientsPlayPrevalenceProtein BiosynthesisProteinsQuality of lifeRecoveryRepressionResearchRoleSignal PathwaySignal TransductionSkeletal MuscleSocietiesStimulusStressTestingWorkXPA geneagedbasedemethylationfallsmuscle formnovelnovel therapeutic interventionolder patientpreventpromoterprotein degradationpublic health relevanceskeletaltherapeutic targetxeroderma pigmentosum group A complementing protein
项目摘要
DESCRIPTION (provided by applicant): Skeletal muscle atrophy is a common disorder caused by aging, illness, muscle disuse and fasting. Frequent and serious effects of skeletal muscle atrophy include weakness, falls, fractures, prolonged hospitalization, insulin resistance, loss of independent living and impaired quality of life. Despite these broad implications for human health, skeletal muscle atrophy remains poorly understood and lacks a pharmacological therapy. In preliminary studies, we identified a molecular signaling pathway that promotes muscle atrophy. In human and mouse skeletal muscle, diverse stresses including aging, illness, muscle disuse and fasting increase the level of Gadd45a protein. Gadd45a then translocates to nuclei of skeletal muscle fibers and stimulates demethylation of the Cdkn1a gene promoter. This activates the Cdkn1a gene and increases the level of Cdkn1a protein. Importantly, Cdkn1a increases protein breakdown, decreases protein synthesis, and ultimately, causes skeletal muscle atrophy. Taken together, these preliminary data reveal a new role for active DNA demethylation in muscle atrophy, and identify Gadd45a-stimulated Cdkn1a demethylation as a critical molecular event. However, the mechanisms that control Cdkn1a methylation in skeletal muscle remain poorly understood. These mechanisms represent potential therapeutic targets for medicines to prevent and treat muscle atrophy in humans who are ill or aged. In the proposed studies, we will use mouse and cultured myotube models to determine molecular mechanisms that control Cdkn1a methylation in skeletal muscle. In Specific Aim 1, we will test the hypothesis that nucleotide excision repair proteins interact with Gadd45a to form multimeric complexes that actively demethylate Cdkn1a and cause muscle atrophy. In Specific Aim 2, we will test the hypothesis that DNA methyltransferase 3a mediates Cdkn1a re-methylation, thereby stimulating the recovery of muscle mass. Through these studies, we hope to discover novel molecular mechanisms that control skeletal muscle mass, as well as new potential therapeutic targets for a disabling condition that affects millions of patients and elderly individuals.
描述(由申请人提供):骨骼肌萎缩是由衰老,疾病,肌肉消失和禁食引起的常见疾病。骨骼肌萎缩的频繁和严重影响包括无力,跌倒,骨折,长时间住院,胰岛素抵抗,独立生活丧失和生活质量受损。尽管对人类健康有着广泛的影响,但骨骼肌萎缩仍然知之甚少,缺乏药理疗法。在初步研究中,我们确定了促进肌肉萎缩的分子信号传导途径。在人和小鼠的骨骼肌中,包括衰老,疾病,肌肉消失和禁食在内的多种应力增加了GADD45A蛋白的水平。然后,GADD45A转移到骨骼肌纤维的核并刺激CDKN1A基因启动子的脱甲基化。这激活了CDKN1A基因并增加了CDKN1A蛋白的水平。重要的是,CDKN1A会增加蛋白质分解,减少蛋白质的合成,并最终导致骨骼肌萎缩。综上所述,这些初步数据揭示了活性DNA在肌肉萎缩中的新作用,并鉴定出GADD45A刺激的CDKN1A脱甲基化是一个关键的分子事件。然而,控制骨骼肌中CDKN1A甲基化的机制仍然鲜为人知。这些机制代表了药物的潜在治疗靶标,以预防和治疗生病或老年人的肌肉萎缩。在拟议的研究中,我们将使用小鼠和培养的肌管模型来确定控制骨骼肌中CDKN1A甲基化的分子机制。在特定的目标1中,我们将测试以下假设:核苷酸切除修复蛋白与GADD45A相互作用,形成积极脱甲基CDKN1A并引起肌肉萎缩的多聚体复合物。在特定目标2中,我们将测试以下假设:DNA甲基转移酶3A介导CDKN1A的重新甲基化,从而刺激肌肉质量的恢复。通过这些研究,我们希望发现控制骨骼肌质量的新型分子机制,以及针对影响数百万患者和老年人的残疾状况的新的潜在治疗靶标。
项目成果
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Michael Dyle其他文献
Michael Dyle的其他文献
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{{ truncateString('Michael Dyle', 18)}}的其他基金
Investigating the Molecular Mechanisms of Skeletal Muscle Atrophy
研究骨骼肌萎缩的分子机制
- 批准号:
8593648 - 财政年份:2013
- 资助金额:
$ 1.09万 - 项目类别:
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