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.

抽象的 代谢压力源和糖尿病等病理状况会导致明显的生理改变 在蛋白质调节中，导致肌肉萎缩，这与发病高度相关。但是， 这种关联的基础机制仍然难以捉摸。了解保持肌肉的机制 蛋白质含量对于改善胰岛素抵抗和整体代谢健康至关重要。脂肪组织是 通过分泌蛋白质，对急性和长期挑战性疾病做出反应的内分泌器官， 称为脂肪因子。有证据表明，脂肪因子介导的信号传导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动作，它们可以被开发为 代谢疾病的治疗剂。虽然已经付出了巨大的努力来瞄准脂肪组织 作为胰岛素抵抗的组成部分，了解脂肪因子参与肌肉生理学。我的 研究培训计划将利用内分泌学，肌肉生物学，生物信息学和新生成的通用 鼠标模型作为工具包，以研究先前理解的马酮的功能和机制 促进肌肉生长，副作用可能更少。该提案检验了一个中心假设，即 Isthmin-1（ISM1）介导调节肌肉蛋白质的脂肪肌肉串扰。以下目标是 提议：目标1：确定ISM1是否通过脂肪肌肉串扰介导肌肉生长。目的 2：确定ISM1是否改变了肌肉蛋白合成和降解之间的平衡。目标3：使用 磷酸蛋白质组学发现调节肌肉蛋白质的新型途径。如果成功，这项研究 将在肌肉生长中建立一种新颖的脂肪肌肉途径，并具有潜在的未来治疗意义， 由于ISM1 Horse1本身可以用作萎缩和疾病的直接药物治疗 哪个练习不是一种选择。 该项目还将为赵博士作为独立研究者的长期目标提供培训 解剖代谢器官之间的马串扰，以改善代谢疾病。候选人博士 赵接受了代谢生理学的广泛且适当的事先培训，其中13个出版物包括5个出版物 自2016年以来的作者。量身定制的职业发展计划使Zhao博士能够获得新的实验技能 以及肌肉生物学，生物化学和专家生理学家的内分泌信号传导的概念， 内分泌学家和心理团队的生物化学家。斯坦福大学的环境无与伦比 进行协作和创新研究和职业发展培训。总而言之 预计环境和培训计划将为Zhao博士做好准备，以启动她的独立职业。这 拟议的研究有望提供对脂肪肌肉串扰的机械见解，以识别治疗 可以对抗肌肉蛋白质流失和相关代谢疾病的靶标。