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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的代谢应激源和糖尿病等病理状况可能导致明显的生理变化蛋白质调节，导致肌肉萎缩，这与发病率高度相关。这种关联背后的机制仍然难以捉摸。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。通过分泌蛋白质来应对急性和慢性能量挑战条件的内分泌器官，称为脂肪因子有证据表明脂肪因子介导的信号在器官中起着至关重要的作用。由于它们的直接信号传导作用，它们可以被开发为串扰和全身能量代谢。针对代谢疾病的治疗剂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。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遗传学小鼠模型作为工具包来研究先前研究过的激素的功能和机制该提议测试了中心假设：促进肌肉生长，并可能减少副作用。 Isthmin-1 (Ism1) 介导调节肌肉蛋白质稳态的脂肪-肌肉串扰，其目标如下。建议：目标 1：确定 Ism1 是否通过脂肪-肌肉串扰介导肌肉生长。 2：确定 Ism1 是否改变肌肉蛋白质合成和降解之间的平衡目标 3：使用。如果成功，这项研究将通过磷酸蛋白质组学来发现调节肌肉蛋白质稳态的新途径。将在肌肉生长中建立一种新型的脂肪-肌肉途径，具有潜在的未来治疗意义，因为 Ism1 激素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个选择。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剖析代谢器官之间的激素串扰以改善代谢疾病。赵博士在代谢生理学方面接受过广泛且适当的培训，发表过 13 篇出版物，其中 5 篇为第一作者自2016年起作为作者。职业发展计划是为使赵博士获得新的实验技能而量身定制的以及专家生理学家在肌肉生物学、生物化学和内分泌信号传导方面的概念，导师团队中有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。总而言之，强有力的指导。预计环境和培训计划将为赵博士开启她的独立职业生涯做好充分准备。拟议的研究有望为脂肪-肌肉串扰提供机制见解，以确定治疗方法可以对抗肌肉蛋白质损失和相关代谢疾病的目标。