4E-BP Dependent Secreted Proteins from Human and Fly Skeletal Muscle
人类和果蝇骨骼肌的 4E-BP 依赖性分泌蛋白
基本信息
- 批准号:8568594
- 负责人:
- 金额:$ 5.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-15 至 2015-09-14
- 项目状态:已结题
- 来源:
- 关键词:AgingAging-Related ProcessAnimal ModelBinding ProteinsBiochemicalBiologicalBody fatCardiovascular DiseasesCellsChestChronic DiseaseComb animal structureComplexDataDevelopmentDietDiseaseDistalDrosophila genusDrosophila melanogasterEndocrineEndocrine GlandsEukaryotic Initiation FactorsExerciseFat BodyGene TargetingGeneticHumanInvertebratesLeadLinkLongevityMammalsMeasuresMediatingMessenger RNAMetabolicMetabolismMethodsMitochondriaModelingMolecularMotor ActivityMusMuscleMuscle CellsMuscle functionNeurodegenerative DisordersNon-Insulin-Dependent Diabetes MellitusOrganismPathway interactionsPhenotypePhysical activityPhysiologicalPlayPreventionProcessProtein OverexpressionProtein SecretionProteinsProteomicsRNA InterferenceRisk FactorsRoleSignal PathwaySirolimusSkeletal MuscleTestingTherapeuticTissuesTranslatingTriglyceride MetabolismWhole OrganismWorkYeastsage relateddietary restrictionfeedingflyimprovedinnovationinsightlipid metabolismmuscle formnovelparacrinepreventprotective effectpublic health relevancereceptorrespiratorysarcopeniatooltranslational approach
项目摘要
DESCRIPTION (provided by applicant): Aging itself is the number one risk factor for a number of chronic diseases, including cardiovascular disease, type 2 diabetes, and neurodegenerative diseases. One physiological hallmark of aging is sarcopenia or the gradual loss of skeletal muscle mass and therefore functions. While the link between aging and muscle mass loss exists across many species, the mechanism by which muscle mass loss or prevention of declining muscle function have not been completely elucidated. Similarly, many of the processes or environmental modifiers, such as dietary restriction (DR), which can protect against the aging process, are conserved from yeast to invertebrate model to vertebrate models, suggesting common molecular, biochemical, and physiological mechanisms. Thus, model organisms, such as the Drosophila Melanogaster, with complex body plans, relatively short life span, powerful genetic tools, and well defined aging phenotypes are ideally situated for
the discovery of new mechanisms of aging. One well defined aging pathway is the target of rapamycin (TOR) pathway, modulation of which has been shown to extend lifespan in yeast, worms, flies and even mice. We and others have recently found that muscle specific modulation of eukaryotic translation initiation factor 4E binding protein (4E-BP), a downstream target of TOR has non-autonomous effects that can alter lifespan and triglyceride metabolism in the fat body. One potential mechanism is through the ability of muscle to secrete proteins with paracrine and endocrine actions. We hypothesize that DR/4E-BP mediate their benefits on healthspan in part through skeletal muscle secreted proteins (myokines) that have tissue specific and whole organism benefits. We also hypothesize that effects of 4E-BP on muscle are conserved between invertebrates and mammals. In order to find conserved targets of 4E-BP that are secreted in the muscle, we propose to use human muscle cells to determine the 4E-BP dependent secreted proteins from skeletal muscle. The list of candidate proteins will be compared with existing data on the 4E-BP dependent differences in translated mRNAs from fly thorax muscle. The combination of human and fly approach should lead to identification of high conserved 4E-BP dependent secreted proteins. Once these proteins have been identified they will be systemically genetically manipulated in fly skeletal muscle to determine whether they are sufficient and/or necessary for the DR/4E-BP benefits on healthspan. In additional we will examine whether manipulation of the targets in muscle is sufficient to alter fat body phenotype and whether blocking of the likely mechanism of action of the target is sufficient or necessary for
the DR/4E-BP benefits on healthspan. Together we believe this is an innovative translational approach that should provide insight into highly conserved biological mechanisms important in aging and age-related chronic diseases. Furthermore, specific proteins identified may have therapeutic potential to prevent/treat a number of age related diseases.
描述(由申请人提供):衰老本身是许多慢性疾病的头号风险因素,包括心血管疾病,2型糖尿病和神经退行性疾病。衰老的一个生理标志是肌肉减少症或骨骼肌质量和功能的逐渐丧失。虽然衰老和肌肉质量损失之间的联系存在于许多物种中,但肌肉质量损失或预防肌肉功能下降的机制尚未完全阐明。同样,许多过程或环境调节剂,如饮食限制(DR),可以防止衰老过程,从酵母到无脊椎动物模型到脊椎动物模型都是保守的,表明共同的分子,生化和生理机制。因此,模式生物,如黑腹果蝇,具有复杂的身体结构,相对较短的寿命,强大的遗传工具,以及明确的衰老表型,是研究的理想场所。
发现衰老的新机制一个明确定义的衰老途径是雷帕霉素(TOR)途径的靶点,其调节已被证明可以延长酵母、蠕虫、苍蝇甚至小鼠的寿命。我们和其他人最近发现,肌肉特异性调节真核生物翻译起始因子4 E结合蛋白(4 E-BP),TOR的下游靶点具有非自主效应,可以改变脂肪体中的寿命和甘油三酯代谢。一个潜在的机制是通过肌肉分泌具有旁分泌和内分泌作用的蛋白质的能力。我们假设DR/4 E-BP通过骨骼肌分泌蛋白(肌因子)介导其对健康寿命的益处,这些蛋白具有组织特异性和整个生物体益处。我们还假设4 E-BP对肌肉的影响在无脊椎动物和哺乳动物之间是保守的。为了寻找4 E-BP在肌肉中分泌的保守靶点,我们建议使用人肌肉细胞来确定骨骼肌中4 E-BP依赖的分泌蛋白。候选蛋白的列表将与现有的数据进行比较的4 E-BP依赖的差异翻译的mRNA从苍蝇胸肌。结合人和苍蝇的方法,将导致高度保守的4 E-BP依赖性分泌蛋白的鉴定。一旦这些蛋白质被鉴定,它们将在苍蝇骨骼肌中进行系统的遗传操作,以确定它们是否足以和/或必要的DR/4 E-BP对健康的益处。此外,我们将检查肌肉中靶点的操纵是否足以改变脂肪体表型,以及靶点的可能作用机制的阻断是否足以或必需改变脂肪体表型。
DR/4 E-BP对健康的益处。我们共同相信这是一种创新的翻译方法,可以深入了解在衰老和与年龄相关的慢性疾病中重要的高度保守的生物学机制。此外,鉴定的特定蛋白质可能具有预防/治疗许多年龄相关疾病的治疗潜力。
项目成果
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Matthew James Laye其他文献
Matthew James Laye的其他文献
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{{ truncateString('Matthew James Laye', 18)}}的其他基金
Highly Conserved 4E-BP Dependent Secreted Proteins from Human and Fly Skeletal Mu
来自人和果蝇骨骼 Mu 的高度保守的 4E-BP 依赖性分泌蛋白
- 批准号:
8703585 - 财政年份:2012
- 资助金额:
$ 5.57万 - 项目类别:
Highly Conserved 4E-BP Dependent Secreted Proteins from Human and Fly Skeletal Mu
来自人和果蝇骨骼 Mu 的高度保守的 4E-BP 依赖性分泌蛋白
- 批准号:
8457666 - 财政年份:2012
- 资助金额:
$ 5.57万 - 项目类别: