Microgravity as model for immunological senescence and its impact on tissue stem cells and regeneration

微重力作为免疫衰老模型及其对组织干细胞和再生的影响

• 批准号: 9507984
• 负责人: Tobias Deuse
• 金额: $ 54.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2019-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507984
• 关键词: Affect; Age; Aging; Aging-Related Process; Antigens; Architecture; B-Lymphocytes; Biological; Biological Process; Biology of Aging; Blood Vessels; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiac; Cardiovascular system; Cell Aging; Cell Culture Techniques; Cell Differentiation process; Cell Maintenance; Cells; Chronic; Clinical; Coculture Techniques; Collaborations; Cues; Data; Defect; Development; Discrimination; Disease; Disease model; Doctor of Philosophy; Elderly; Endothelial Cells; Environment; Experimental Models; Frequencies; Future; Health; Histologic; Homing; Human; Immune; Immune response; Immune system; Immunological Models; Impairment; In Vitro; Individual; Infiltration; International; Investigation; Mediating; Memory; Mesenchymal; Microgravity; Microgravity Simulation; Modeling; Molecular; Myocardial; Natural regeneration; Neurodegenerative Disorders; Neurologic; Organ; Organism; Outcome; Pathogenicity; Pathway interactions; Phase; Physiological; Physiology; Planet Earth; Process; Proliferating; Recovery; Scientist; Signal Transduction; Space Flight; Space Medicine; Stem cells; Stromal Cells; Structure; Surgeon; System; T cell differentiation; T-Lymphocyte; Technology; Tissue Microarray; Tissues; Translating; Validation; adaptive immunity; aged; base; bone healing; cell behavior; cytokine; design; experimental study; extracellular; functional genomics; healing; immune function; immunosenescence; improved; in vivo; in vivo Model; inflammatory milieu; injured; insight; novel; organ regeneration; osteogenic; pathogen; peripheral blood; pre-clinical; receptor; regenerative; repaired; response; response to injury; role model; senescence; space station; systems research; tissue culture; tissue regeneration; tool

PROJECT SUMMARY Aging is associated with dysregulation of the immune response, which is also termed “immunosenescence.” Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected, and it is especially the T cells that are altered. In fact, the number and proportion of late-differentiated T cells, particularly CD8+ T cells, is higher in the elderly than in the young and their accumulation may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in elderly individuals. Interestingly, the proportion of CD8+ effector memory RA (TEMRA) cells increases significantly with age, which is not seen for CD4+ cells. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. Spaceflight causes a suite of negative health effects that may be comparable to immunosenescence, which seems to be a key regulator of the regenerative capacity of tissue- and organ-specific stem cells. Organ-specific stem and progenitor cells may allow the design of strategies for organ regeneration. The overarching objective of this proposal is to gain a better understanding of the influence of immunosenescence on the regenerative capacity of tissue-specific stem cells. Specifically, studies examining the effects of bone healing (by mesenchymal stromal cells) and vascular regeneration (by endothelial progenitor cells) are planned using tissue mimics on chip to represent “semi-3D” architectures. Ultimately, we will use microgravity as an aging model, and we will translate those findings to improve human health on Earth by using tissue chips on the ISS for up to a month. Notably, the proposed studies investigate post-flight recovery of tissue chips using histological analysis combined with functional and genomic analysis. In collaboration with Space Technology and Advanced Research Systems, Inc. - STaARS, well-versed in maintenance of cell culture experiments in spaceflight, we are establishing an in vitro tissue-on-chip platform that mimics human physiology to study the effect of immunosenescence on tissue-specific stem cells. This system will be designed for use in the UH3 phase in the extreme environment of space. In the UG3 phase, we will examine the effect of simulated microgravity and normal (1xg) conditions on in vitro cultures of CD8+ T cells and on their co-culture with stem cells (UG3 Aim 1). In UG3 Aim 2 we will investigate the effect of microgravity at the International Space Station – National Lab (ISS-NL) on in vitro co-cultures of CD8+ T cells and stem cells. In the UH3 phase, we will determine the effect of microgravity on immunosenescence (differentiation of CD8+ T cells into TEMRA cells) and tissue-specific stem cells in space as model for aging using microarrays (UH3 Aim 1). Finally, in UH3 Aim 2, we will investigate post-flight recovery of tissue chips (from Aim 1, UH3 phase) using functional analysis of stem cells. This proposal will contribute materially to our understanding of the impact of an aged immune system on tissue healing and regeneration.

项目总结 衰老与免疫反应的失调有关，也被称为“免疫衰老”。 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，获得性免疫 似乎受到更广泛的影响，尤其是T细胞发生了变化。事实上，这个数字和 老年人晚期分化T细胞，尤其是CD8+T细胞的比例高于年轻人和 它们的积累可能有助于增强老年人常见的全身促炎环境。 个人。有趣的是，CD8+效应记忆RA(TEMRA)细胞的比例随着 年龄，这在CD4+细胞中是看不到的。我们不知道到底是什么导致了这些观察到的变化，但 对可能原因的理解现在开始浮出水面。航天飞行导致一系列负面健康 可能与免疫衰老相媲美的效果，免疫衰老似乎是再生能力的关键调节因素 组织和器官特异性干细胞的能力。器官特异的干细胞和祖细胞可能会允许这种设计 器官再生的策略。这项建议的主要目的是为了更好地了解 免疫衰老对组织特异性干细胞再生能力的影响。具体来说， 研究考察骨愈合(通过间充质基质细胞)和血管再生(通过 内皮祖细胞)是使用芯片上的组织模拟来表示“半3D”结构来规划的。 最终，我们将使用微重力作为衰老模型，我们将把这些发现转化为改善人类 通过在国际空间站使用组织芯片长达一个月来保护地球的健康。值得注意的是，拟议的研究调查了 使用组织学分析结合功能和基因组分析对组织芯片进行飞行后回收。在……里面 与空间技术和高级研究系统公司合作-STAARS，精通 维持航天中的细胞培养实验，我们正在建立一个体外组织芯片平台 它模仿人类的生理学，研究免疫衰老对组织特异性干细胞的影响。这 该系统将被设计用于在极端空间环境中的UH3阶段。在UG3阶段，我们 将检测模拟微重力和正常(1xg)条件对CD8+T细胞体外培养的影响 与干细胞共培养(UG3目标1)。在UG3目标2中，我们将研究微重力的影响 在国际空间站国家实验室(ISS-NL)进行了CD8+T细胞和干细胞的体外共培养。 在UH3阶段，我们将确定微重力对免疫衰老(CD8+T细胞分化)的影响 利用微阵列(UH3目标1)在太空中建立衰老模型(UH3目标1)。 最后，在UH3目标2中，我们将研究组织芯片的飞行后回收(从目标1，UH3阶段)使用 干细胞的功能分析。这项建议将大大有助于我们了解 衰老的免疫系统对组织愈合和再生的影响。