Characterization of the Insulin to Autophagy Pathway in Muscles

肌肉中胰岛素自噬途径的表征

• 批准号: 10426200
• 负责人: NORBERT PERRIMON
• 金额: $ 51.3万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426200
• 关键词: Activities of Daily Living; Adult; Affect; Aging; Anorexia; Atrophic; Automobile Driving; Autophagocytosis; Biogenesis; Biology; Cachexia; Cells; Cessation of life; Defect; Degradation Pathway; Diabetes Mellitus; Disease; Drosophila genus; Elderly; Equilibrium; Event; Exercise; FRAP1 gene; Fibroblast Growth Factor; Genes; Genetic Transcription; Growth; Heart Diseases; Homeostasis; Human body; IGF1 gene; Injury; Insulin; Label; Lysosomes; Maintenance; Malignant Neoplasms; Metabolism; Methods; Midgut; Modeling; Molecular; Morphology; Muscle; Muscle Contraction; Muscular Atrophy; Organelles; Organism; Pathway interactions; Phenotype; Play; Process; Protein Biosynthesis; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; RNA; Regulation; Risk; Role; Signal Pathway; Signal Transduction; Sirolimus; Skeletal Muscle; Study models; System; Systemic disease; Tissues; Tumor-Derived; Ubiquitin; age related; aged; cancer cachexia; fly; frailty; insight; mitochondrial dysfunction; multicatalytic endopeptidase complex; muscle form; muscle strength; novel; nutrition; obesity risk; protein aggregation; protein degradation; response; sarcopenia; skeletal muscle wasting; transcription factor; tumor; wasting

SUMMARY / ABSTRACT Understanding the molecular mechanisms underlying muscle growth and wasting is highly relevant to conditions such as anorexia, sarcopenia, and diseases such as cachexia. Muscle size is regulated by the coordinated balance between protein synthesis and degradation. The IGF1-AKT-mTOR axis is a central player in regulating increase in protein synthesis by stimulating the translational machinery while simultaneously blocking protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway. Drosophila muscle is a well-established system to study the maintenance of muscle mass, TOR signaling and autophagy. We have recently identified two new RNA biogenesis signaling pathways that regulate autophagy and metabolism downstream of TOR. In Aim 1, we will characterize RNA biogenesis processes regulated by TOR signaling in muscles, focusing on the regulation of autophagy and metabolism. In addition, we have established the adult fly midgut as a model to study tumor-induced host wasting. This model has allowed us to precisely follow transcriptional changes and morphological events leading to muscle wasting. In Aim 2, we will characterize the role of REPTOR, a transcription factor downstream of TOR, that we hypothesize acts as a “master regulator of cachexia” and will characterize its regulation and target genes. We will also analyze the role of mitophagy in muscle wasting. Finally, we have identified three factors, ImPL2, PvF1, and Upd3, derived from gut tumors that contribute to muscle wasting. We will characterize the role of an additional pathway, the Branchless/FGF pathway. In addition, we will perform a proteomic screen using a novel proximity labeling method to identify additional factors derived from tumors that affect wasting. Altogether, our studies will reveal novel cell autonomous and non-autonomous molecular mechanisms involved in the regulation of muscle mass. Considering the high level of conservation between Drosophila and higher organisms our studies are likely to help in the long term to devise treatments of conditions such as anorexia, sarcopenia and cachexia.

总结/摘要 了解肌肉生长和萎缩的分子机制与以下方面高度相关： 诸如厌食症、肌肉减少症的病症和诸如恶病质的疾病。肌肉的大小是由 蛋白质合成和降解之间的协调平衡。IGF 1-AKT-mTOR轴是一个核心球员 通过刺激翻译机制来调节蛋白质合成的增加，同时 阻断蛋白质降解途径、泛素-蛋白酶体系统和自噬-溶酶体 通路果蝇肌肉是研究肌肉质量（TOR）维持的成熟系统 信号传导和自噬。我们最近发现了两条新的RNA生物合成信号通路， 调节TOR下游的自噬和代谢。在目标1中，我们将描述RNA生物合成 肌肉中TOR信号调节的过程，专注于自噬和代谢的调节。在 此外，我们还建立了果蝇中肠模型来研究肿瘤诱导的宿主消瘦。该模型 使我们能够精确地跟踪导致肌肉萎缩的转录变化和形态学事件。 在目标2中，我们将描述REPTOR（TOR下游的一种转录因子）的作用， hypothesize作为“恶病质的主要调节因子”，并将表征其调节和靶基因。我们 还将分析线粒体自噬在肌肉萎缩中的作用。最后，我们确定了三个因素，ImPL 2， PvF 1和Upd 3，来源于导致肌肉萎缩的肠道肿瘤。我们将描述一个 另外的途径，无分支/FGF途径。此外，我们将使用一种新的蛋白质组学筛选方法， 邻近标记方法，以确定来自肿瘤的影响消耗的其他因素。总的来说， 我们的研究将揭示新的细胞自主和非自主的分子机制， 调节肌肉质量。考虑到果蝇和高等植物之间的高度保守性， 从长远来看，我们的研究可能有助于设计厌食症等疾病的治疗方法， 肌肉减少症和恶病质。