ISS: Tissue Engineered Liver Immune Chips in Microgravity as a Novel Platform to Study the Effect of Aging

衰老与身体免疫反应的受损有关。免疫系统的每个部分都在一定程度上受到衰老过程的影响。然而，适应性免疫，使我们能够消除疾病产生因子（病原体）或防止其生长的免疫，似乎受到更广泛的影响。 因此，对感染的易感性增加，对疫苗接种的反应差，以及自身反应性（针对身体自身组织的免疫反应）的发生率增加。目前尚不清楚是什么原因导致了这些观察到的变化，但现在开始了解可能的原因。许多与空间有关的生理变化类似于在衰老过程中观察到的变化。然而，在微重力暴露之后，这种变化在重返地球后或多或少会很快恢复。该项目旨在研究个体的免疫衰老和愈合结果之间的关系，并从两个方向研究衰老的生物学-不仅在微重力条件下的发展过程中，而且在恢复过程中。组织芯片设计成像人体器官一样工作，模仿活的人体组织和细胞。研究人员将使用组织芯片设计，使他们能够探索肝脏衰老和再生与免疫反应之间的关系，并寻找减缓衰老过程和增强肝脏愈合过程的可能方法。每个免疫系统芯片包括两种类型的细胞：特定类型的免疫细胞和与免疫细胞相互作用的肝细胞。通过将芯片送入太空，研究人员将能够模拟免疫系统的老化过程，并了解随着年龄的增长，它如何影响我们肝脏的自我修复能力。这项研究有望为许多人类疾病的分子基础提供新的见解，在这个特定的项目中，这与微重力如何诱导免疫系统老化有关，这可能导致地球上新疗法的发展。为了实现科学目标，该项目将与伯克利的空间科学实验室合作，总结细胞芯片的电镀方式，并记录太空体验的每一步：从发射到储存在国际空间站（ISS），直到样本返回。细胞工程的结果和概念将通过一套新的在线资源传播给广大受众。 教育目标包括吸引学生到许多STEM学科，让他们参与对古老的，迷人的问题的尖端调查，包括延长人类寿命，以及地球以外其他地方可能的长期人类存在，并通过吸引和连接不仅教育工作者和学生，这项研究的首要目标是更好地了解免疫衰老的影响，即与衰老有关的人体免疫反应的失调。适应性免疫似乎特别受到终末分化的CD 8+效应记忆T（TEMRA）细胞频率增加的影响，这是由慢性抗原暴露驱动的，并与衰老相关。 许多与空间有关的生理变化类似于在老化期间观察到的变化，但在重返后恢复。 研究人员已经证明，模拟微重力诱导T细胞分化为TEMRA细胞，分别影响间充质干细胞和上皮祖细胞（EPC）在伤口愈合和管形成中的修复能力。该项目的重点是更好地了解免疫衰老对肝脏特异性干细胞再生能力的影响。 所有实验将利用组织芯片上的肝组织模拟物（CD 8 + T细胞和肝祖细胞（LPC）的体外3D共培养物）。最终，这些芯片将被放置在国际空间站长达一个月，微重力将作为老化模型。 研究计划是根据两个目标组织的。 第一个目的是研究老年CD 8 + T细胞对肝脏祖细胞行为、可塑性和空间修复能力的影响，并评估个体免疫反应性与愈合之间的关系。 对于这些研究，在太空中一个月后，芯片将被固定/冷冻，以便随后进行飞行后分析。 第二个目的是利用功能分析研究组织芯片的飞行后恢复。 对于这些研究，在太空中一个月后，随着微重力老化组织的恢复，芯片将从太空返回进行飞行后分析。这些综合目标使人们能够调查衰老的生物学--不仅是其发展，而且是其逆转。所获得的数据预计将为T细胞老化对肝脏干细胞的影响以及随后的肝脏愈合和再生提供重要的见解，这将为未来在肝脏中与年龄相关的改变患者中使用提供新的治疗范例。（国际空间站上的项目集成和操作将由空间科学促进中心（CASIS）的执行伙伴BioServe提供。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估的支持。

Aging is associated with impairment of the body's immune response. Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity, the immunity that allows us to eliminate disease producing agents (pathogens) or prevent their growth, seems more extensively affected. As a result, there is increased susceptibility to infection, poor responses to vaccination, and increased incidence of autoreactivity (immune responses directed against the body's own tissues). It is not known exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. Many space-related physiological changes resemble those observed during aging. However, following microgravity exposure, such changes are more or less quickly restored after re-entry to Earth. This project aims to investigate the relationship between an individual's immune aging and healing outcomes, and to investigate the biology of aging from two directions--not only during its development in microgravity conditions but also during recovery. Designed to work like human organs, tissue chips mimic living human tissues and cells. The investigators will use a tissue chip design that enables them to explore the relationship between liver aging and regeneration and immune responses and to look for possible ways to slow the aging process and enhance the liver healing process. Each immune system chip includes two types of cells: a specific type of immune cell and liver cells, which interact with the immune cells. By sending the chips into space, the investigators will be able simulate the aging process of the immune system and understand how it affects our liver's ability to repair itself as we grow older. This research is expected to provide new insights into the molecular basis for many human conditions, which in this particular project relates to how microgravity induces aging of the immune system that may lead to the development of novel therapies here on Earth. In tandem with the scientific objectives, the project will work with the Space Sciences Laboratory at Berkley to summarize how cell chips are plated and document each step of the space experience: from launch, to storage on the International Space Station (ISS), until sample return. The results and the concept of cellular engineering will be disseminated to a broad audience through a suite of new online resources. The education goals include attracting students to the many STEM disciplines by engaging them with cutting-edge investigations on age-old, fascinating questions that include extending the human lifespan, and possible long-term human existence elsewhere beyond Earth and strengthening educators' and the public's support of this and other NSF-funded research by drawing in and connecting not only educators and students, but the general public to exciting medical research taking place aboard the ISS.The overarching goal of this research thrust is to gain a better understanding of the influence of immunosenescence, the dysregulation of the body's immune response, which is associated with aging. Adaptive immunity seems particularly affected by the increase in the frequency of terminally differentiated CD8+ effector memory T (TEMRA) cells, which is driven by chronic antigen exposure and correlates with aging. Many space-related physiological changes resemble those observed during aging but are restored after re-entry. The investigators have already demonstrated that simulated microgravity induces the differentiation of T cells into TEMRA cells that impact the repair capacity of mesenchymal stem cells and epithelial progenitor cells (EPCs) in wound healing and tube formation, respectively. The focus of this project is to gain a better understanding of the influence of immunosenescence on the regenerative capacity of liver-specific stem cells. All experiments will utilize liver tissue mimics (in vitro 3D-co-cultures of CD8+ T cells and Liver Progenitor Cells (LPCs)) on tissue chips. Ultimately, the chips will be placed in the ISS for up to a month, where microgravity will serve as the aging model. The Research Plan is organized under two objectives. The First Objective is to study the effect of aged CD8+ T cells for liver progenitor cells behavior, plasticity, and repair capacity in space and to assess the relationship between an individual's immune reactivity and healing. For these studies, after the month in space, the chips will be fixed/frozen for subsequent post-flight analysis. The Second Objective is to investigate post-flight recovery of tissue chips using functional analysis. For these studies, after the month in space, the chips will be returned live from space for post-flight analysis as the microgravity aged tissues recover. The combined objectives enable investigation of the biology of aging--not only its development but also its reversal. The data obtained are expected to provide important insights into the influence of T cell aging on liver stem cells and subsequent liver healing and regeneration that will lead to a new treatment paradigm for future use in patients with age-associated alteration in the liver. (Project integration and operation on the ISS will be provided by the Center for the Advancement of Science in Space (CASIS) implementation partner, BioServe.)This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.