Asthma, anxiety and GR abnormalities in non-human primates

非人类灵长类动物的哮喘、焦虑和 GR 异常

• 批准号: 8839569
• 负责人: ANGELA HACZKU
• 金额: $ 21.09万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839569
• 关键词: 2 year old; Allergens; Allergic; Animals; Anxiety; Asthma; Biological Models; Blood specimen; Brain; California; Cells; Cellular Stress; Child; Chronic; Chronic stress; DNA Binding; DNA Methylation; Data; Dexamethasone; Disease; Epigenetic Process; Exhibits; Exons; Extrinsic asthma; Gene-Modified; Genes; Genetic; Glucocorticoid Receptor; Glucocorticoids; Histone H3; Human; Hydrocortisone; IgE; Immune; Infant; Inflammatory; Institutes; Interleukin-12; Investigation; Lead; Link; Lung; Lysine; Macaca mulatta; Maps; Methylation; Mission; Modeling; Modification; Molecular; Monkeys; Mus; NF-kappa B; NR3C1 gene; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Environmental Health Sciences; National Institute of Mental Health; Nuclear Translocation; Pathway interactions; Peripheral Blood Eosinophilia; Peripheral Blood Mononuclear Cell; Predisposition; Primates; Psychosocial Factor; Psychosocial Stress; Receptor Gene; Regulation; Research; Research Personnel; Rodent; Role; Steroids; Stress; Temperament; United States National Institutes of Health; airway hyperresponsiveness; airway inflammation; anxious temperament; brain cell; cohort; histone modification; human disease; inhibitor/antagonist; mRNA Expression; methylation pattern; mouse model; nonhuman primate; peripheral blood; promoter; psychosocial; psychosocial development; public health relevance; receptor expression; social; social stress; transcription factor

 DESCRIPTION (provided by applicant): We previously demonstrated that allergen-induced airway inflammation and hyper responsiveness (AHR) was enhanced in mice exposed to repeated social stress. We also found that chronic social disruption stress in mice caused impaired glucocorticoid receptor (GR) expression and function in immune cells and in the lung. By other investigators stress was shown to induce abnormal methylation pattern of the GR gene and modified H3K4me3 and H3K27me3 in brain cells of rodents. The significance and mechanisms of the chronic psychosocial stress effects on the GR remain unclear and the currently available chronic models of psychosocial stress in rodents are less than optimal. In non-human primates (rhesus macaques) studied at the CNPRC at UC Davis, inhibited temperament in infant monkeys was associated with blunted cortisol responsiveness and AHR at 2 years of age. We postulate that a heightened predisposition to asthma of chronically stressed rhesus macaques is related to an impaired responsiveness to endogenous glucocorticoids. We further hypothesize that presence of stress (manifested as inhibited temperament) and allergic asthma (elevated IgE, peripheral blood eosinophilia and AHR) increases NF-kB activity that interferes with the GR in immune cells. Epigenetic modifications of the Exon 1 gene promoter reduce GR expression in stressed animals. Aim 1 is to study whether increased NF-kB activity interferes with GR expression, function and steroid responsiveness of peripheral blood immune cells from primates that exhibit chronic anxiety and asthma. We will compare glucocorticoid responsiveness and expression of GR and NF-kB (a pro-inflammatory transcription factor and GR inhibitor), nuclear translocation and DNA binding in peripheral blood mononuclear cells from these four groups. Aim 2 is to study the role of epigenetic changes in regulation of GR expression in immune cells of primates that exhibit stress and AHR. We previously found stress-induced reduction in GR mRNA expression in the lung of mice. Stress-induced DNA methylation of NR3C1 and histone modifications was also identified in rodents. In peripheral blood mononuclear cells from rhesus macaques we will correlate abnormal GR expression with gene methylation patterns using DNA methylation mapping and ChIPseq analysis. These studies will lay the groundwork for subsequent investigations into the relevance to human disease and mechanistic studies on the cellular-molecular pathways that lead to asthma predisposition due to psychosocial stress.

 描述（由申请人提供）：我们之前证明，在反复受到社会压力的小鼠中，过敏原诱导的气道炎症和高反应性（AHR）增强。我们还发现，小鼠的慢性社会破坏压力会导致糖皮质激素受体（GR）表达受损。其他研究人员发现，压力会诱导啮齿动物脑细胞中 GR 基因的异常甲基化模式和 H3K4me3 和 H3K27me3 的修饰。慢性心理社会压力对 GR 影响的机制仍不清楚，目前啮齿类动物的慢性心理社会压力模型并不理想。在加州大学戴维斯分校 CNPRC 研究的非人类灵长类动物（恒河猴）中，婴儿的气质受到抑制。猴子在 2 岁时与皮质醇反应性和 AHR 减弱有关，我们假设长期处于应激状态的恒河猴的哮喘易感性与内源性反应性受损有关。我们进一步注意到压力（表现为抑制性气质）和过敏性哮喘（IgE 升高、外周血嗜酸性粒细胞增多和 AHR）会增加 NF-kB 活性，从而干扰免疫细胞中 GR 的表观遗传修饰。目的 1 是研究 NF-kB 活性的增加是否会干扰灵长类动物外周血免疫细胞的 GR 表达、功能和类固醇反应。我们将比较这四组的外周血单核细胞中的糖皮质激素反应性和 GR 和 NF-kB（一种促炎转录因子和 GR 抑制剂）的表达、核易位和 DNA 结合。研究表观遗传变化在表现出应激和 AHR 的灵长类动物免疫细胞中 GR 表达的调节作用，我们之前发现应激诱导的小鼠肺部 GR mRNA 表达减少。在恒河猴的外周血单核细胞中也发现了 NR3C1 和组蛋白修饰，我们将使用 DNA 甲基化作图和 ChIPseq 分析将异常 GR 表达与基因甲基化模式相关联。这些研究将为后续研究与人类的相关性奠定基础。对因社会心理压力导致哮喘易感性的细胞分子途径进行疾病和机制研究。