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
• 负责人: Matthew James Laye
• 金额: $ 5.47万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703585
• 关键词: Aging; Aging-Related Process; Animal Model; Binding Proteins; Biochemical; Biological; Body fat; Cardiovascular Diseases; Cells; Chest; Chronic Disease; Comb animal structure; Complex; Data; Development; Diet; Disease; Distal; Drosophila genus; Drosophila melanogaster; Endocrine; Endocrine Glands; Eukaryotic Initiation Factors; Exercise; Fat Body; Gene Targeting; Genetic; Human; Invertebrates; Lead; Link; Longevity; Mammals; Measures; Mediating; Messenger RNA; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Molecular; Motor Activity; Mus; Muscle; Muscle Cells; Muscle function; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathway interactions; Phenotype; Physical activity; Physiological; Play; Prevention; Process; Protein Overexpression; Protein Secretion; Proteins; Proteomics; RNA Interference; Risk Factors; Role; Signal Pathway; Sirolimus; Skeletal Muscle; Testing; Therapeutic; Tissues; Translating; Triglyceride Metabolism; Whole Organism; Work; Yeasts; age related; dietary restriction; feeding; fly; improved; innovation; insight; lipid metabolism; muscle form; novel; paracrine; prevent; protective effect; public health relevance; receptor; respiratory; sarcopenia; skeletal; tool; translational approach

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危险因素，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逐渐丧失，从而丧失功能。虽然许多物种都存在衰老和肌肉质量损失之间的联系，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，许多可以防止衰老过程的过程或环境调节剂，如饮食限制（DR），从酵母到无脊椎动物模型再到脊椎动物模型都是保守的，这表明了共同的分子、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、强大的遗传工具和明确的衰老表型，是理想的选择