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

描述(由申请人提供)：这份建议书描述了一个为期5年的项目，它将促进我成为一名独立调查员的职业目标。我提出了一项培训和职业发展计划，其中包括一项对肌肉生理学和人类疾病的理解具有重大影响的研究建议，实验室技术培训，以及有助于研究战略和职业发展的基础研讨会。我将得到C·罗纳德·卡恩博士的指导，他是胰岛素信号领域的世界领先者，他培养了160多名科学家，其中许多人是该领域的领导者。此外，我还组建了一个优秀的委员会，听取科学和职业建议。我将在乔斯林糖尿病中心接受培训，这是哈佛大学的一个附属机构，也是优秀研究的中心。我这个项目的目标是了解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型糖尿病的特征，但也发生在失控的1型糖尿病和危重疾病中。与这些情况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)传递的信号可促进蛋白质合成和抑制降解，但在正常和糖尿病条件下，胰岛素或IGF-1信号抑制肌肉萎缩或改变线粒体功能的相对作用和机制尚未完全阐明。我的初步数据显示，在没有葡萄糖稳态改变的情况下，肌肉中IR和IGFR的丢失会显著减小肌肉尺寸，增加自噬的标志，并损害肌肉功能。目标1将破译IR或IGFR信号在肌肉蛋白质代谢和自噬中的相关作用。目的2将发现IR/IGFR信号的下游靶点，介导糖尿病和肌肉胰岛素抵抗时蛋白质周转和自噬细胞流量的变化。目的3将确定改变的IR和IGFR信号在肌肉线粒体功能和线粒体的自噬细胞清除，或“有丝分裂”中的作用。这项研究将阐明胰岛素抵抗的作用，改变 IGF-1信号转导和糖尿病对肌肉蛋白质代谢的影响，并有望找到既能减少肌肉萎缩又能增强线粒体功能的治疗靶点。

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.