Regulation of Muscle Autophagy and Mitophagy by Insulin and IGF-1 Signaling

胰岛素和 IGF-1 信号传导对肌肉自噬和线粒体自噬的调节

• 批准号: 8730651
• 负责人: Brian Timothy O'Neill
• 金额: $ 14.45万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730651
• 关键词: Affect; Amino Acids; Atrophic; Autophagocytosis; Complement; Critical Illness; Data; Development Plans; Diabetes Mellitus; Diabetic mouse; Disease; Exhibits; Fasting; Functional disorder; Genus Hippocampus; Goals; Health; Hormones; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Label; Laboratories; Lysosomes; Measurement; Measures; Mediating; Mentors; Metabolic; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; Myoblasts; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathway interactions; Physiology; Protein Biosynthesis; Protein Isoforms; Proteins; Receptor Signaling; Recycling; Regulation; Relative (related person); Research; Research Personnel; Research Proposals; Role; Scientist; Sepsis; Serum; Signal Transduction; Signaling Molecule; Skeletal Muscle; Staining method; Stains; Starvation; Techniques; Testing; Time; Training; Transfection; Ubiquitin; blood glucose regulation; career; career development; diabetic; glucose disposal; human disease; in vivo; insulin signaling; mitochondrial dysfunction; multicatalytic endopeptidase complex; muscle form; prevent; protein degradation; protein metabolism; public health relevance; receptor; receptor-mediated signaling; research study; response; small hairpin RNA; therapeutic target

DESCRIPTION (provided by applicant): This proposal describes a 5 year project which will facilitate my career goals to become an independent investigator. I put forth a training and career development plan which includes a research proposal with strong implications on the understanding of muscle physiology and human disease, training in laboratory techniques, and fundamental seminars to aide in research strategy and career development. I will be mentored by Dr. C. Ronald Kahn, a world leader in the field of insulin signaling, who has trained greater than 160 scientists many of whom are leaders in their field. Additionally, I have assembled an excellent committee for scientific and career advice. I will train at Joslin Diabetes Center, an affiliate of Harvard, an epicenter of excellent research. The goal of my project is to understand the role of IGF-1 and insulin signaling in muscle protein metabolism and mitochondrial function. Muscle insulin resistance and mitochondrial dysfunction are hallmarks of type 2 diabetes, but also occur in uncontrolled type 1 diabetes and critical illness. Muscle atrophy associated with these conditions is detrimental to health. Signaling via the insulin receptor (IR) and the closely related IGF-1 receptor (IGFR) enhances protein synthesis and inhibits degradation, yet the relative contribution and mechanisms by which insulin or IGF-1 signaling inhibits muscle atrophy or alters mitochondrial function under normal and diabetic conditions have not been fully elucidated. My preliminary data show that loss of both IR and IGFR in muscle dramatically decreases muscle size, increases markers of autophagy, and impairs muscle function in the absence of altered glucose homeostasis. Aim 1 will decipher the relative roles of IR or IGFR signaling on muscle protein metabolism and autophagy. Aim 2 will discover the downstream targets of IR/IGFR signaling that mediate the alterations in protein turnover and autophagocytic flux in response to diabetes and muscle insulin resistance. Aim 3 will determine the role of altered IR and IGFR signaling on muscle mitochondrial function and autophagocytic clearance of mitochondria, or "mitophagy". This study will elucidate the roles of insulin resistance, altered IGF-1 signaling and diabetes on muscle protein metabolism and hopefully identify therapeutic targets to both decrease muscle atrophy and enhance mitochondrial function.

描述（由申请人提供）：本提案描述了一个5年的项目，这将有助于我的职业目标，成为一名独立的调查员。我提出了一个培训和职业发展计划，其中包括对肌肉生理学和人类疾病的理解具有强烈影响的研究建议，实验室技术培训，以及帮助研究战略和职业发展的基本研讨会。我将接受C博士的指导。罗纳德卡恩是胰岛素信号领域的世界领导者，他培养了160多名科学家，其中许多人是各自领域的领导者。此外，我还组建了一个优秀的科学和职业建议委员会。我将在乔斯林糖尿病中心接受培训，该中心是哈佛的附属机构，是优秀研究的中心。我的项目的目标是了解IGF-1和胰岛素信号在肌肉蛋白质代谢和线粒体功能中的作用。肌肉胰岛素抵抗和线粒体功能障碍是2型糖尿病的标志，但也发生在不受控制的1型糖尿病和危重病中。与这些病症相关的肌肉萎缩对健康有害。通过胰岛素受体（IR）和密切相关的IGF-1受体（IGFR）的信号传导增强蛋白质合成并抑制降解，但胰岛素或IGF-1信号传导在正常和糖尿病条件下抑制肌肉萎缩或改变线粒体功能的相对贡献和机制尚未完全阐明。我的初步数据显示，在没有改变葡萄糖稳态的情况下，肌肉中IR和IGFR的缺失显著减小肌肉尺寸，增加自噬标记物，并损害肌肉功能。目的1阐明IR或IGFR信号通路在肌肉蛋白质代谢和自噬中的相关作用。目的二是寻找IR/IGFR信号通路的下游靶点，这些靶点介导糖尿病和肌肉胰岛素抵抗引起的蛋白质周转和自噬流量的改变。目的3将确定改变的IR和IGFR信号对肌肉线粒体功能和线粒体自噬清除或“线粒体自噬”的作用。这项研究将阐明胰岛素抵抗的作用，改变 IGF-1信号传导和糖尿病对肌肉蛋白质代谢的影响，并有望确定治疗靶点，以减少肌肉萎缩和增强线粒体功能。