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：
10209269
负责人：
Siobhan Malany
金额：
$ 47.2万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10209269
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 age-related muscle loss 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.

项目概要本拨款申请响应 RFA-TR-18-001“NIH-CASIS 协调微生理系统” 空间转化研究计划”提出了杰出的合作努力桑福德伯纳姆普雷比斯医学发现研究所、SpacePharma, INC、佛罗里达医院的研究人员佛罗里达大学代谢与糖尿病转化研究所生物医学工程和空间技术和高级研究系统（STaARS）。长期太空飞行后会出现肌肉退化，但这些影响在很大程度上是可逆的；随着年龄的增长，观察到骨骼肌的内在变化，例如 DNA 损伤、细胞应激、线粒体功能障碍和衰老可能与微重力诱导的细胞机制重叠。使用人体组织模拟疾病状况的微重力研究可能会极大地促进发展解决老年人肌肉萎缩（称为肌少症）的临床相关方法。 60岁以上老年人数量正以前所未有的速度增长，约占全球人口的11% 到 2050 年，目前的人口将增加到约 21%。部分治疗肌肉减少症的治疗方案相对不存在由于对控制与年龄相关的骨骼肌的机制的不完全了解我们的团队一直致力于开发微流体芯片实验室系统来研究人类。我们建立了微重力下骨骼肌细胞生长和基因表达的变化。从年轻、健康和年老、久坐的志愿者中分离出原代人类肌细胞的条件，并已生物学数据表明细胞保留了供体组织的表型。制造了一个带有多个培养室的飞行芯片，我们计划将其纳入该提案中。将电极插入芯片并通过模拟确定电场强度分布，以优化条件电刺激嵌入天然模仿细胞外基质中的肌肉细胞。芯片将集成到远程控制的全自动实验室解决方案中，并配备流体处理系统、记录收缩的光学检测系统以及近实时的软件平台在 STaARS-1 实验飞行设施中的国际空间站上进行的实验控制在随后的飞行中，我们建议在经过验证的芯片实验室系统中测试具有抗萎缩特性的天然产物。通过添加能够递送的管理端口将促进向肌肉培养物的递送我们的下一代芯片实验室系统将成为小型化实验室的领导者。疾病模型来研究微重力引起的肌肉组织的病理生理变化，旨在药物功效和毒理学测试促进了治疗方法的发展，以减轻肌肉萎缩的负担。