3D micro-physiological systems for identification of therapeutic myokines

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 肌因子尽管转译的潜力巨大，但由于血液传播因子的动态性质， 这些体液因子的可靠鉴定仍然是一个主要障碍。为了克服这一挑战，张博士和 博士Park的团队将利用先进的微工程方法来构建3D微流体肌肉回路 它可以控制生理相关的3D微环境中的机械和生物化学线索。在这 根据这项提案，两个研究小组将通过整合细胞类型特异性 蛋白质标记系统（MetRSL 2774 G转基因），以精确鉴定负责肌肉分泌的蛋白质组。 肌肉与远程器官的通讯此外，该团队还将设计一种运动诱导的肌因子 使用与蛋白质标记共表达的光遗传学致动器（Eschel-rhodopsin 2）的报告系统 构建体，MetRSL 274 G。使用这些方法，拟议的研究将确定新的收缩诱导 肌因子，负责运动的有益效果。最后，研究小组试图确定 肌肉蛋白质组对肌肉-心脏串扰发挥作用，特别是在缺血性心脏病的背景下， 预处理该项目的成功结果将对肌肉生物学产生深远而广泛的影响 和医药这种微创3D微生理系统可用于各种研究 测试全身组织的相互作用更重要的是，经过验证，本研究中使用的实验方法 该提案可以转化为开发基于肌因子的治疗迟发性生活方式障碍的药物。

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.