Investigating Isthmin as an adipose-to-muscle messenger that promotes muscle protein synthesis

研究 Isthmin 作为促进肌肉蛋白质合成的脂肪到肌肉信使

• 批准号: 10664500
• 负责人: Meng Zhao
• 金额: $ 9.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-14 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664500
• 关键词: Ablation; Acute; Adipocytes; Adipose tissue; Atrophic; Biochemistry; Bioinformatics; Biological Assay; Biology; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Conceptions; Data; Degradation Pathway; Development Plans; Diabetes Mellitus; Disease; Endocrine; Endocrine Glands; Endocrinologist; Endocrinology; Energy Metabolism; Environment; Enzyme-Linked Immunosorbent Assay; Equilibrium; Exercise; FRAP1 gene; Fiber; Fibroblasts; Fracture; Future; Genes; Genetic; Genetic Transcription; Goals; Growth; Health; Hormonal; Hormones; Human; In Vitro; Insulin Resistance; Knock-in; Knockout Mice; Liver; Maps; Mediating; Mentors; Metabolic; Metabolic Diseases; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Proteins; Muscle function; Muscular Atrophy; Nutrient; Obesity; Organ; PIK3CG gene; Pathologic; Pathway interactions; Persons; Pharmacological Treatment; Phosphorylation; Physiological; Physiology; Play; Point Mutation; Postdoctoral Fellow; Protein Biosynthesis; Protein Secretion; Protein Synthesis Induction; Proteins; Proto-Oncogene Proteins c-akt; Publications; Regulation; Research; Research Personnel; Research Training; Risk; Role; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Source; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Training; Universities; Western Blotting; Wild Type Mouse; Work; adipokines; bioinformatics tool; career; career development; experimental study; glucose uptake; improved; in vivo; innovation; insight; mouse model; muscle form; muscle physiology; novel; pharmacologic; phosphoproteomics; protein biomarkers; protein degradation; proteostasis; receptor; research and development; response; sensor; side effect; skills; stressor; therapeutic target

ABSTRACT Metabolic stressors and pathologic conditions such as diabetes can lead to pronounced physiologic alterations in protein regulation, resulting in muscle atrophy, which is highly associated with morbidity. However, the mechanisms underlying this association remain elusive. Understanding the mechanisms of maintaining muscle protein content is crucial to improving insulin resistance and overall metabolic health. Adipose tissue is an endocrine organ that responds to acute and chronic energetically challenging conditions by secreting proteins, referred to as adipokines. Evidence suggests that signaling mediated by adipokines plays a crucial role in organ crosstalk and systemic energy metabolism. Because of their direct signaling action, they can be developed as therapeutic agents for metabolic diseases. While considerable effort has been made to target the adipose tissue as a component of insulin resistance, the involvement of adipokines in muscle physiology is understudied. My research training plan will leverage endocrinology, muscle biology, bioinformatics, and newly generated genetic mouse models as a toolkit to investigate the function and mechanisms of a previously understudied hormone in promoting muscle growth with potentially fewer side effects. This proposal tests the central hypothesis that Isthmin-1 (Ism1) mediates adipose-muscle crosstalk that regulates muscle proteostasis. The following aims are proposed: Aim 1: To determine whether Ism1 mediates muscle growth through adipose-muscle crosstalk. Aim 2: To determine whether Ism1 alters balance between muscle protein synthesis and degradation. Aim 3: Using phosphoproteomics to discover novel pathways that regulate muscle proteostasis. If successful, this research will establish a novel adipose-muscle pathway in muscle growth with potential future therapeutic implications, since the Ism1 hormone itself can be used as a direct pharmacologic treatment for atrophy and disorders for which exercise is not an option. This project will also provide training for Dr. Zhao’s long-term goal as an independent investigator to dissect the hormonal crosstalk between metabolic organs to improve metabolic diseases. The candidate Dr. Zhao has extensive and suitable prior training in metabolic physiology, with 13 publications including 5 as first- author since 2016. The Career Development Plan is tailored to enable Dr. Zhao to gain new experimental skills and concepts in muscle biology, biochemistry, and endocrine signaling from expert physiologists, endocrinologists, and biochemists in the mentoring team. The environment at Stanford University is unparalleled for collaborative and innovative research and career development training. In summary, the strong mentoring environment and training plan are anticipated to fully prepare Dr. Zhao to launch her independent career. The proposed studies promise to offer mechanistic insights into adipose-muscle crosstalk to identify therapeutic targets that can counter muscle protein loss and associated metabolic disease.

摘要 代谢应激源和糖尿病等病理情况会导致明显的生理变化。 在蛋白质调节中，导致肌肉萎缩，这与发病率高度相关。然而， 这种联系背后的机制仍然难以捉摸。了解维持肌肉的机制 蛋白质含量对改善胰岛素抵抗和整体新陈代谢健康至关重要。脂肪组织是一种 内分泌器官，通过分泌蛋白质来对急性和慢性能量挑战条件做出反应， 被称为脂肪因子。有证据表明，脂肪因子介导的信号在器官中起着至关重要的作用 串扰和全身能量代谢。由于它们的直接信号作用，它们可以发展为 代谢性疾病的治疗剂。虽然已经做出了相当大的努力来靶向脂肪组织 作为胰岛素抵抗的一个组成部分，脂肪因子在肌肉生理学中的作用尚未得到充分研究。我的 研究培训计划将利用内分泌学、肌肉生物学、生物信息学和新产生的基因 小鼠模型作为工具箱来研究以前未被研究的激素的功能和机制 促进肌肉生长，副作用更少。这一提议检验了核心假设，即 Isthmin-1(ISM1)介导脂肪-肌肉串扰，调节肌肉蛋白平衡。以下是目标 建议：目的1：确定ISM1是否通过脂肪-肌肉串扰来调节肌肉生长。目标 2：确定ISM1是否改变了肌肉蛋白质合成和降解之间的平衡。目标3：使用 磷酸蛋白质组学，以发现调节肌肉蛋白平衡的新途径。如果成功，这项研究 将在肌肉生长中建立一种新的脂肪-肌肉途径，具有潜在的未来治疗意义， 由于ISM1激素本身可以用作治疗萎缩和疾病的直接药物治疗 哪种锻炼不是一种选择。 该项目还将为赵博士作为独立调查员的长期目标提供培训 剖析代谢器官之间的荷尔蒙串扰，以改善代谢性疾病。这位候选人是Dr。 赵先生曾接受过广泛和适当的代谢生理学培训，发表了13篇论文，其中5篇是首次发表- 自2016年以来一直是作者。职业发展计划是为了让赵博士获得新的实验技能而量身定做的 以及来自专业生理学家的肌肉生物学、生化和内分泌信号方面的概念， 指导团队中的内分泌学家和生物化学家。斯坦福大学的环境是无与伦比的 用于协作和创新的研究和职业发展培训。总而言之，强大的导师 环境和培训计划预计将为赵博士开始她的独立职业生涯做好充分准备。这个 拟议的研究承诺提供对脂肪-肌肉串扰的机械性见解，以确定治疗方法 可以对抗肌肉蛋白质丢失和相关代谢性疾病的靶点。