Suppression of the Immune Response in Spaceflight and Aging

太空飞行和衰老过程中免疫反应的抑制

• 批准号: 8727822
• 负责人: MILLIE HUGHES-FULFORD
• 金额: $ 9.2万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727822
• 关键词: Affect; Aging; Altered Gravity; Astronauts; Bacterial Infections; Bioinformatics; CD4 Positive T Lymphocytes; Candidate Disease Gene; Clinical; Collection; Contracts; Data; Depressed mood; Disease; Double-Stranded RNA; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Epithelium; Fever Chills; Force of Gravity; Gel; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Head; Herpes zoster disease; Human; Humanities; Immune; Immune response; Immune system; Immunosuppression; In Vitro; Infection; Interleukin-2; International; Lymphocyte; Measures; MicroRNAs; Microarray Analysis; Microgravity; Mission; Modeling; Molecular; Ocular orbit; Older Population; Persons; Pharmacologic Substance; Phase; Production; Promoter Regions; Protein Biosynthesis; Proteins; Proteomics; Pseudomonas aeruginosa; Quantitative Reverse Transcriptase PCR; Quarantine; Regulation; Reporting; Research; Research Personnel; Signal Transduction Pathway; Simulate; Sodium Dodecyl Sulfate-PAGE; Space Flight; State of Zero Gravity; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Time; United States National Aeronautics and Space Administration; United States National Institutes of Health; Viral; Virus Diseases; Western Blotting; Work; age related; base; experience; immune function; in vivo; innovation; interest; novel; overexpression; pathogen; programs; research study; transcription factor

Project Summary In aging, immune systems falter and the elderly are more susceptible to infection. Age related changes include decreased T-cell activation/proliferation, decreased production of IL-2 and decreased expression of IL-2R¿. These are the same key immune changes that are seen in returning astronauts who have experienced altered immune function and increased vulnerability to infection during spaceflights. Loss of immune response in aging and spaceflight has been previously identified in T cells. We have previously identified microgravity induced changes in gene expression, promoter regions, transcription factors and signal transduction pathways in human CD4+ T-cells under normal and altered gravity conditions. Our preliminary data from International Space Station (ISS) described within this proposal show that in early T-cell activation at least one miRNA was upregulated during activation in normal gravity (g), while in microgravity (¿g), the induction of the miRNA was muted. Moreover, three protein targets of the miRNA had increased expression in the 1.g environment suggesting a micro RNA mechanism. The changes in immune function in the elderly occur over time and are hard to evaluate. However, the same type of changes in immune response occurs microgravity, both in astronauts and in human T-cells and is easy to measure The central hypothesis is that ¿g regulates MiRNA in human T-cells and that weightlessness is a novel model to study the immunosuppression seen in aging. These experiments will contribute to our fundamental understanding of the molecular mechanism of immunosuppression in spaceflight and in aging. The Specific Aims are the following: (1) Identify gene expression of miRNAs during T-cell activation (using arrays and qRTPCR) under normal gravity. (2) Identify the MiRNA(s) target genes using bioinformatics and verify the changes in expression of those targets messages (qRTPCR). We will test the ability of microgravity to induce/reduce expression of MiRNAs and their targets and verify these results using miRNA overexpression viral constructs or dsRNA. (3) Analyze the protein synthesis of the upregulated/downregulated target genes (SDS PAGE gels and Western Blot proteomics) that are affected by T-cell activation under normal gravity and microgravity conditions. (4) Compare the expression of key MiRNAs candidates and genes after activation in normal gravity and microgravity, vs. that of the lymphocytes from an older population.

项目摘要 随着年龄的增长，免疫系统会衰退，老年人更容易受到感染。年龄相关变化 包括T细胞活化/增殖减少、IL-2产生减少和减少 IL-2R的表达。这些与在返回中看到的关键免疫变化相同 经历了免疫功能改变和感染易感性增加的宇航员 在太空飞行中。衰老和航天中免疫反应的丧失以前已经 在T细胞中被鉴定。我们之前已经发现了微重力引起的基因表达的变化， 人CD4+T细胞的启动子区域、转录因子和信号转导途径 在正常和变化的重力条件下。我们来自国际空间站的初步数据 该提案中描述的(ISS)表明，在T细胞早期激活中，至少有一种miRNA是 在正常重力(G)激活期间上调，而在微重力(？g)下，诱导 MiRNA被静音。此外，miRNA的三个蛋白质靶标在1.g 环境暗示了一种微型RNA机制。老年人免疫功能的变化 随着时间的推移而发生，而且很难评估。然而，相同类型的免疫反应变化 在宇航员和人类T细胞中都发生了微重力，并且很容易测量中央 假说是G调节人类T细胞中的miRNA，失重是一种新的模型 研究衰老过程中出现的免疫抑制现象。这些实验将有助于我们从根本上 了解航天和衰老中免疫抑制的分子机制。 具体目标如下：(1)确定T细胞活化过程中miRNAs的基因表达 (使用阵列和qRTPCR)在正常重力下。(2)鉴定S的miRNA靶基因 生物信息学，并验证这些靶信息表达的变化(QRTPCR)。我们将测试 微重力诱导/减少miRNAs及其靶点表达的能力及其验证 结果使用miRNA过表达病毒构建物或dsRNA。(3)蛋白质合成分析。 上调/下调的靶基因(SDS PAGE凝胶和Western Blot蛋白质组学)是 在正常重力和微重力条件下受T细胞激活的影响。(4)比较 在正常重力和微重力条件下激活后关键miRNAs候选和基因的表达， 而不是来自老年人群的淋巴细胞。