3D micro-physiological systems for identification of therapeutic myokines

用于识别治疗性肌因子的 3D 微生理系统

基本信息

批准号：
10595294
负责人：
Young Charles Jang
金额：
$ 53.41万
依托单位：
EMORY 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：
2023-05-22 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595294
关键词：
3-Dimensional Accounting Acute Animal Model Arteries Binding Biochemical Biological Markers Biological Models Biological Process Biology Biomimetics Biopsy Blood Cardiac Cardiovascular Diseases Categories Cell physiology Cells Chemistry Chronic Circulation Communication Cues Dementia Detection Disease Dose Endocrine Endocrine Glands Engineering Exercise Exercise Therapy Factor Analysis Genetic Goals Hindlimb Human body Hypoxia In Vitro Ischemia Ischemic Preconditioning Label Left Life Style Ligation Limb structure Malignant Neoplasms Mechanics Medicine Methionine-tRNA Ligase Microfluidics Muscle Muscle Contraction Muscle Proteins Myocardial Ischemia Myocardium Myopathy Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Optics Organ Outcome Patients Physical activity Physiological Point Mutation Post-Translational Protein Processing Protein Biosynthesis Proteins Proteome Proteomics Reporter Reporting Research Rhodopsin Role Sampling Second Messenger Systems Skeletal Muscle System Testing Therapeutic Time Tissues Tourniquets Transgenes Translating Validation Vascularization Work cell type cost effective cytokine detection platform endurance exercise exercise regimen exercise training in vivo innovation microphysiology system minimally invasive mouse model muscle regeneration myogenesis novel optogenetics protective effect public health relevance receptor sarcopenia sedentary skeletal spatiotemporal tool translational potential treadmill

项目摘要

PROJECT SUMMARY Skeletal muscle is a highly vascularized tissue that can secrete cytokines and proteins, collectively termed as myokines. Despite the tremendous potential for translation, due to the dynamic nature of blood-borne factors, reliable identification of these humoral factors remains a major hurdle. To overcome this challenge, Dr. Jang and Dr. Park’s group will leverage advanced microengineering approaches to build a 3D microfluidic muscle circuit that can control mechanical and biochemical cues in the physiologically relevant 3D microenvironment. In this proposal, two groups will further refine and upgrade the in vitro muscle platform by integrating a cell-type-specific protein labeling system (MetRSL2774G transgene) to precisely identify the muscle secretome responsible for the muscle-to-remote organ communications. In addition, the team will also engineer an exercise-induced myokine reporter system using an optogenetic actuator (Channel-rhodopsin 2) co-expressed with protein labeling construct, MetRSL274G. Using these approaches, proposed studies will identify novel contraction-induced myokines that are responsible for the beneficial effects of exercise. Finally, the research team seeks to identify muscle proteomes that exert their action on muscle-heart crosstalk, especially in the context of ischemic preconditioning. The successful outcomes of this project will have far and broad implications in muscle biology and medicine. This minimally invasive 3D microphysiological system can be exploited in a variety of studies testing systemic tissue interactions. More importantly, upon validation, the experimental approach used in this proposal can be translated to develop myokine-based therapeutics for late-onset lifestyle disorders.

项目摘要骨骼肌是一种高度血管化的组织，可以分泌细胞因子和蛋白质，统称为 Myokines。尽管翻译的潜力巨大，但由于血传播因素的动态性质，这些体液因素的可靠识别仍然是一个重大障碍。为了克服这一挑战，张博士和 Park博士的小组将利用先进的微工程方法来构建3D微流体肌肉电路可以控制物理相关的3D微环境中的机械和生化线索。在这个提案，两组将通过整合细胞类型特异性来进一步完善和升级体外肌肉平台蛋白质标记系统（metrsl2774g转基因），以确定负责肌肉的肌肉分泌组肌肉到象征器官通信。此外，团队还将设计运动引起的肌动物使用光遗传执行器（通道 - ropopsin 2）与蛋白质标记共表达的记者系统构造，metrsl274g。使用这些方法，拟议的研究将确定新的收缩诱导负责运动的有益作用的肌动物。最后，研究小组试图确定肌肉蛋白质组织对肌肉心脏的串扰作用，尤其是在缺血性的背景下预处理。该项目的成功结果将对肌肉生物学具有广泛的影响和医学。可以在各种研究中探索这种最小的侵入性3D微生物生理系统测试全身组织相互作用。更重要的是，经过验证，使用的实验方法可以翻译提出的建议以开发基于肌基的治疗治疗，以用于晚期的生活方式障碍。