Electrical Stimulation of Human Myocytes in Microgravity: An In Vitro Model to Evaluate Therapeutics to Counteract Muscle Wasting

微重力下人体心肌细胞的电刺激：评估对抗肌肉萎缩治疗方法的体外模型

基本信息

批准号：
9788552
负责人：
Siobhan Malany
金额：
$ 48.47万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-21 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788552
关键词：
Address Adult Age Aging Applications Grants Area Astronauts Athletic Atrophic Attenuated Biological Biological Models Biomedical Engineering Cells Cellular Stress Collaborations Computer software Contracts DNA Damage Data Detection Development Devices Diabetes Mellitus Disease Progression Disease model Drug Delivery Systems Drug Screening Elderly Electric Stimulation Electrodes Environment Exposure to Extracellular Matrix FDA approved Florida Functional disorder Gene Expression Goals Health Care Costs Hospitals Human Hydrogels Hypogravity In Vitro Individual Institutes International Intervention Island Lab-On-A-Chips Laboratories Liquid substance Manuals Medical Metabolism Microgravity Modeling Molecular Monitor Muscle Muscle Cells Muscle Fibers Muscular Atrophy Natural Products Older Population Optics Pathway interactions Pharmaceutical Preparations Pharmacology Study Phase Phenotype Physical Performance Physiological Planet Earth Population Process Property Protocols documentation Pulse Rates Quality of life Research Research Institute Research Personnel Sampling Skeletal Muscle Space Flight Specialist System Technology Testing Therapeutic Time Tissue Donors Tissue Engineering Tissues Toxicology Translational Research United States National Institutes of Health Universities age related aged cell growth cell type clinical development clinically relevant design drug candidate drug discovery drug efficacy electric field experimental study human tissue improved in vitro Model microphysiology system miniaturize mitochondrial dysfunction multidisciplinary muscle aging muscle degeneration muscle form muscle strength next generation novel therapeutics physiologic model prevent response safety assessment sarcopenia sedentary senescence simulation skeletal muscle wasting space station systems research therapeutic development therapeutic evaluation transcriptome translational research program volunteer

项目摘要

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 Sanford Burnham Prebys Medical Discovery Institute, SpacePharma, INC, Florida Hospital Translational Research Institute for Metabolism and Diabetes, the University of Florida Department of Biomedical Engineering and Space Technology and Advanced Research Systems (STaARS). 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 relatively non-existent in part because of an incomplete understanding of the mechanisms controlling age-related skeletal muscle dysfunction. Our team has been focused on developing a 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 incorporate electrodes into the chip and determine electric field strength distribution by simulation to optimize conditions for electrically stimulating muscle myocytes embedded in a native mimicking extracellular matrix. Our lab-on-a- chip will be integrated into a remote controlled, fully automated laboratory solution 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 STaARS-1 experimental flight facility. On a subsequent flight, we propose to test natural products with anti-atrophy properties in the validated lab-on-a-chip system. 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 lab-on-a-chip 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 of therapeutics to elevate the burden of muscle wasting.

项目摘要此赠款应用于RFA-TR-18-001“ NIH-CASIS协调的微生物生理系统在太空中转化研究计划”，提案是在佛罗里达州SpacePharma的Sanford Burnham Prebys医疗发现研究所的调查人员佛罗里达大学代谢和糖尿病转化研究所生物医学工程和太空技术以及高级研究系统（Staars）。宇航员长时间太空飞行后患有肌肉变性。这些影响在很大程度上是可逆的。但是，观察到年龄的骨骼肌的内在变化，例如DNA损伤，细胞应激，线粒体功能障碍和感应可能与微重力诱导的细胞机制重叠。那，使用人体组织进行微重力研究对疾病状况进行建模可能会极大地有助于发展临床上相关的方法来解决肌肉浪费的方法，称为肌肉减少症。 60岁以上的基本个人的数量正在以前所未有的速度增长。今天的人口到2050年。由于对控制年龄相关的骨骼肌肉的机制不完全理解功能障碍。我们的团队一直专注于开发一个毫米芯片的实验室来研究人类骨骼肌细胞的生长和基因表达在微重力中变化。我们已经建立了文化从年轻，健康和年长，久坐的志愿者中分离出的原发性肌细胞的疾病生物学数据表明细胞保留了供体组织的表型。此外，我们还有用多个文化室制造了一个准备飞行的筹码。对于此提案，我们计划合并电极进入芯片，并通过模拟确定电场强度分布，以优化电刺激的肌肉心肌细胞嵌入模仿天然的细胞外基质中。我们的实验室芯片将集成到遥控，全自动实验室解决方案中，并配有流体处理系统，一个光学检测系统记录收缩，以及用于近实时的软件平台控制STAARS-1实验飞行设施中ISS的实验。在随后的飞行中，我们建议在经过验证的实验室芯片系统中测试具有抗芳香特性的天然产物。药品将通过增加能够交付的管理端口来准备向肌肉培养多种药物稀释。我们的下一代实验室芯片系统将成为小型实验室的领导者疾病建模以研究微博的肌肉组织的病理生理变化，旨在提高药物效率和毒理学测试，以提高肌肉浪费的燃烧。