Deposition of data from ground and flight samples for sarcopenia MPS system

奖学金项目摘要 本资助申请，响应RFA-TR-18-001“NIH-CASIS协调 空间转化研究微生理系统计划”，提出了一个 佛罗里达大学的研究人员之间的杰出合作努力， 药学与工程和AdventHealth转化研究所。宇航员 在长时间的太空飞行后肌肉退化。这些影响主要是 可逆的;然而，随着年龄的增长，骨骼肌中观察到的内在变化，如DNA 损伤、细胞应激、线粒体功能障碍和衰老可能会重叠 在微重力环境下产生的细胞机制。因此，利用人体进行微重力研究， 组织来模拟疾病状况可以极大地促进临床相关的 解决被称为肌肉减少症的老年人肌肉萎缩的方法。的 60岁以上的老年人数量正以前所未有的速度增长， 到2050年，全球人口的约11%将降至约21%。治疗肌肉减少症的治疗选择 部分原因是对这些机制的不完全理解， 控制与年龄相关的骨骼肌功能障碍。我们的团队开发了一种2D毫流体 用于研究人类骨骼肌细胞生长和基因表达的芯片实验室系统 微重力的变化。我们建立了原代人心肌细胞的培养条件 从年轻的、健康的和年长的、久坐的志愿者中分离出来， 表明细胞保留了供体组织的表型。此外，我们有 制作了一个具有多个培养室的飞行准备芯片。对于这项建议，我们计划 开发微生理学（MPS）3D系统，并将电极纳入芯片。我们 将使用COMSOL建模确定电场强度分布，并优化 电刺激嵌入天然细胞外基质中的肌细胞的条件 矩阵我们的MPS将被集成到一个远程控制的全自动实验室中 配有液体处理系统、记录收缩的光学检测系统，以及 一个软件平台，用于对国际空间站上的实验进行近实时控制， TangoLab实验飞行设施。在随后的飞行中，我们建议测试自然 经验证MPS中具有抗萎缩特性的产品。药物输送至肌肉 通过增加能够递送多种药物的给药口， 药物稀释。我们的下一代MPS系统将成为小型化实验室的领导者 疾病建模，以研究肌肉组织中诱导的病理生理学变化， 微重力旨在提高药物疗效和毒理学测试，以治疗肌肉萎缩。

PARENT GRANT PROJECT SUMMARY This grant application, in response to RFA-TR-18-001 “NIH-CASIS Coordinated Microphysiological Systems Program for Translational Research in Space”, proposes an outstanding collaborative effort among investigators at the University of Florida, College of Pharmacy and Engineering and AdventHealth Translational Research Institute. Astronauts suffer from muscle degeneration after prolonged spaceflight. These effects are largely reversible; however, the intrinsic changes in skeletal muscle observed with age such as DNA damage, cellular stress, mitochondrial dysfunction and senescence are likely to overlap with cellular mechanisms induced in microgravity. Thus, studies in microgravity using human tissue to model disease conditions may greatly contribute to development of clinically relevant approaches to address muscle wasting in the elderly referred to as sarcopenia. The number of elderly individuals over the age of 60 is growing at an unprecedented rate from ~11% of the global population today to ~21% by 2050. Therapeutic options to treat sarcopenia are non-existent in part because of an incomplete understanding of the mechanisms controlling age-related skeletal muscle dysfunction. Our team has developed a 2D millifluidic lab-on-a-chip system to study human skeletal muscle cell growth and gene expression changes in microgravity. We have established culture conditions for primary human myocytes isolated from young, healthy and older, sedentary volunteers and have biological data indicating that the cells retain the phenotype of the donor tissue. Furthermore, we have fabricated a flight ready chip with multiple culture chambers. For this proposal, we plan to develop a microphysiological (MPS) 3D system and incorporate electrodes into the chip. We will determine electric field strength distribution using COMSOL modeling and optimize conditions for electrically stimulating muscle myocytes embedded in a native extracellular matrix. Our MPS will be integrated into a remote controlled, fully automated laboratory complete with a fluid handling system, an optical detection system to record contraction, and a software platform for near real-time control of the experiment on the ISS housed in the TangoLab experimental flight facility. On a subsequent flight, we propose to test natural products with anti-atrophy properties in the validated MPS. Drug delivery to the muscle cultures will be facilitated via the addition of an administration port capable of delivering multiple drug dilutions. Our next generation MPS system stands to be a leader in miniaturized lab disease modeling to study pathophysiological changes in muscle tissue induced in microgravity intended to advance drug efficacy and toxicological testing to treat muscle wasting.