Replicating heterochronic parabiosis on a chip for testing anti-geronic factors

在芯片上复制异时联体共生以测试抗老年因子

• 批准号: 9914196
• 负责人: Young Charles Jang
• 金额: $ 15.78万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914196
• 关键词: 3-Dimensional; Address; Adolescent; Adult; Age; Aging; Animals; Biochemical; Biophysics; Blood; Blood Circulation; Blood Transfusion; Cardiac Myocytes; Cell Count; Cell physiology; Cells; Characteristics; Clinical Research; Detection; Devices; Ectopic Expression; Elderly; Engineering; Environment; Exposure to; Follow-Up Studies; GDF11 gene; Geroscience; Goals; Growth Factor; Growth and Development function; Human; In Vitro; Injury; Mediating; Membrane; Microfluidics; Mitotic; Modeling; Mus; Muscle; Muscle Development; Muscle function; Muscle satellite cell; Neurons; Operative Surgical Procedures; Outcome; Parabiosis; Plasma; Population; Preclinical Testing; Property; Proteins; Proteomics; Quality of life; Regenerative response; Regulation; Regulatory Pathway; Rejuvenation; Reporting; Skeletal Muscle; Somatotropin; System; Technology; Testing; Therapeutic; Time; Tissues; Translating; Trauma; Validation; Work; age-related muscle loss; aged; aging population; body system; design; drug discovery; drug efficacy; in vivo; innovation; middle age; muscle aging; muscle engineering; muscle form; muscle regeneration; myogenesis; novel; organ on a chip; postnatal; postnatal development; protective factors; regenerative; repaired; resilience; restoration; sarcopenia; satellite cell; screening; skeletal muscle wasting; stem; stem cells; tissue reconstruction; tool; transcription factor

PROJECT SUMMARY Function and regenerative potential of skeletal muscle decline with age, where loss of skeletal muscle quality is attributed to reduced muscle stem (satellite) cell number and function. Inadequate regenerative response following muscle injuries in an aging population further exacerbate the progression of sarcopenia, and therefore reduced independence and quality of life. Exciting studies using the heterochronic parabiosis model, in which young and aged animals are surgically attached to share circulation, suggest the presence of youthful factors in the circulation can rejuvenate age-acquired deficits in muscle regeneration. Subsequent studies have identified a handful of systemic pro-geronic factors, but discovery of the humoral rejuvenation factors that act on muscle stem cells to restore regenerative function has been relatively more elusive. In this context, emerging evidence suggests that during postnatal growth and development, a period of exceptional regenerative capacity and plasticity are maintained in post-mitotic cells. However, the exact identity and underlying pro-regenerative mechanisms are poorly understood. These juvenile protective factors can be manifested as systemic growth factors or presented as circulating progenitor cells. The working hypothesis of this proposal is that these juvenile pro-regenerative factors decrease with aging and ectopic expression of these factors in circulation will elicit superior rejuvenation effects on aged muscle. Despite tremendous therapeutic promise, the critical barrier that limits the detection of putative anti-geronic factors in circulation is the lack of in vitro tools that recapitulates the dynamic regulation of systemic factors in vivo. Thus, it has been technically challenging to design mechanistic studies and elucidate the function of blood-borne factors on their target tissues. To overcome this challenge, the objective in aim 1 is to engineer a novel 3-dimensional (3D) microfluidic “parabiosis-on-a-chip” circuit that harnesses the key characteristics of native muscle microenvironment and systemic circulation. By leveraging parabiosis-on-a-chip platform with in vivo validation and proteomics, this innovative system will facilitate detection of novel humoral factors and cells that are responsible for rejuvenation effects in heterochronic parabiosis. As such, aim 2 will address whether exposure to the juvenile systemic milieu in aged muscle by parabiosis confers superior rejuvenation effects both in vitro and in vivo. Successful outcomes from proposed studies will have high and broad implications not only in Geroscience but also in broad scientific fields. Parabiosis-on-a-chip circuit will provide a state-of-the-art pre-clinical testing tool that will facilitate our understanding of the dynamic regulation of circulating humoral factors and can also be utilized as a screening device for drug discovery. More importantly, parabiosis-on-a-chip can be expanded to study other organ systems and translated into human clinical studies by emulating human parabiosis-on-a-chip that blood transfusion cannot recapitulate.

项目摘要 随着年龄的增长，骨骼肌的功能和再生潜力下降，骨骼肌的损失 质量下降归因于肌肉干（卫星）细胞数量和功能的减少。再生不足 老年人群中肌肉损伤后的反应进一步加剧了肌肉减少症的进展， 从而降低了独立性和生活质量。令人兴奋的研究使用异时共生模型， 年轻和年老的动物通过手术连接在一起，共享循环，这表明年轻的动物存在。 循环中的因子可以使肌肉再生中的年龄获得性缺陷恢复活力。随后的研究 确定了一些系统的pro-geronic因素，但发现体液返老还童的因素， 肌肉干细胞恢复再生功能一直相对更加难以捉摸。在此背景下，新兴 有证据表明，在出生后的生长和发育期间， 和可塑性在有丝分裂后的细胞中得以维持。然而，确切的身份和潜在的亲再生 机制知之甚少。这些青少年保护因子可以表现为全身性生长 因子或呈现为循环祖细胞。这项建议的工作假设是，这些青少年 促再生因子随着年龄的增长而减少，这些因子在循环中的异位表达将引起 对老化肌肉有上级的再生效果。尽管有着巨大的治疗前景， 限制了循环中推定的抗衰老因子的检测是缺乏体外工具， 体内系统因子的动态调节。因此，在技术上具有挑战性的是， 研究和阐明了血源性因子对靶组织的作用。为了克服这一挑战， 目的1的目的是设计一种新颖的三维（3D）微流体“芯片上抛物面”电路， 利用天然肌肉微环境和体循环的关键特征。通过利用 具有体内验证和蛋白质组学的芯片上抛物面反射平台，这一创新系统将促进 检测新的体液因子和细胞，负责在异时再生效应 共生因此，目标2将解决是否暴露于青少年全身环境中的老年肌肉， 共生在体外和体内均赋予上级的再生效果。成功的结果，从拟议的 这些研究不仅在老年科学领域，而且在广泛的科学领域都将具有重大而广泛的意义。 片上寄生虫电路将提供最先进的临床前测试工具， 了解循环体液因子的动态调节，也可用作筛选 用于药物发现的设备。更重要的是，芯片上的抛物面可以扩展到研究其他器官系统 并通过模拟人体寄生虫芯片转化为人类临床研究， 无法概括。