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）：该提案描述了一个为期 5 年的项目，该项目将促进我成为一名独立研究者的职业目标。我提出了一项培训和职业发展计划，其中包括对理解肌肉生理学和人类疾病有重大影响的研究提案、实验室技术培训以及有助于研究策略和职业发展的基础研讨会。我将受到胰岛素信号传导领域的世界领先者 C. Ronald Kahn 博士的指导，他培训了 160 多名科学家，其中许多人都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。我将在哈佛大学附属的乔斯林糖尿病中心接受培训，那里是优秀研究的中心。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，但也出现在未受控制的 1 型糖尿病和危重疾病中。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) 的信号传导可增强蛋白质合成并抑制降解，但胰岛素或 IGF-1 信号传导在正常和正常情况下抑制肌肉萎缩或改变线粒体功能的相对贡献和机制糖尿病的病症尚未完全阐明。我的初步数据表明，在没有改变葡萄糖稳态的情况下，肌肉中 IR 和 IGFR 的丧失会显着减少肌肉大小，增加自噬标记，并损害肌肉功能。目标 1 将破译 IR 或 IGFR 信号传导对肌肉蛋白质代谢和自噬的相对作用。目标 2 将发现 IR/IGFR 信号传导的下游靶标，这些靶标可调节蛋白质周转和自噬细胞通量的变化，以应对糖尿病和肌肉胰岛素抵抗。目标 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，有望确定减少肌肉萎缩和增强线粒体功能的治疗靶点。