Social Regulation of Gene Expression

描述（由申请人提供）：研究一再表明，缺乏社会关系会增加健康状况不佳的风险。最近的研究表明，精神和身体健康状况不佳与社会孤立远端相关，与感知到的社会孤立近端相关，并且无法用健康行为的差异来解释。最近的研究发现，白细胞炎症生物学的下丘脑-垂体-肾上腺（HPA）轴调节的改变是隔离相关健康风险的潜在机制。报告长期高度主观社会隔离的个体表现出早晨皮质醇水平升高（Adams等人，2006年），糖皮质激素靶基因和NF-:B靶基因的全基因组转录发生改变（Cole等人，2007年）。这些与分离相关的白细胞生物学变化可能源于分离人群中糖皮质激素受体（GR）的功能性脱敏（Cole 2008），而这反过来又与NF-:B表达相互相关，而NF-:B是调节细胞对感染、癌症和炎症反应的关键因素。糖皮质激素反应基因的转录受损和促炎转录控制途径的活性增加，为长期高度感知社会孤立的个体炎症性疾病风险升高提供了功能基因组解释。最初的基因组学分析测试了一个相对较小的样本，并为这一假设提供了初步支持。这一修订后的应用程序旨在通过(1)扩大基因组分析的范围，(2)确定糖皮质激素介导的转录控制驱动这些效应的具体方面，(3)确定主观社会隔离在纵向研究中预测转录控制的因果作用的合理性，以及(4)建立主观社会隔离的动物模型，可以为实验研究提供平台。利用芝加哥健康、老龄化和社会关系纵向研究的参与者，一个基于人群的中年和老年人样本，我们调查转录改变是否只发生在那些表现出长期高水平主观隔离的人身上，或者是否类似的影响即使在最小或可变的主观隔离水平上也会发生。GR和/或NF-:B蛋白的差异表达，和/或GR的翻译后修饰（例如，GR磷酸化）将作为糖皮质激素转录控制改变的潜在分子机制进行研究。将通过检查主观隔离在两年期间自然发生的变化在多大程度上预测转录控制的变化来评估社会隔离因果作用的合理性。最后，将通过社会行为分析来评估非人灵长类动物模型，以区分和确定成年雄性恒河猴“社交”表型的稳定性，并通过生物学分析来确定社会表型与HPA活性、GR介导的信号转导和全基因组转录谱之间的关系。

DESCRIPTION (provided by applicant): Research has repeatedly shown that a lack of social ties increases risk for poor health. Recent research has demonstrated that poor mental and physical health outcomes are distally associated with social isolation, are more proximally associated with perceived social isolation, and are not explicable in terms of differences in health behaviors. Recent studies have identified alterations in hypothalamic-pituitary-adrenal (HPA) axis regulation of inflammatory biology in leukocytes as a potential mechanism of isolation-related health risks. Individuals reporting chronically high levels of subjective social isolation have shown a heightened rise in morning cortisol levels (Adams et al. 2006), and alterations in genome-wide transcription of glucocorticoid target genes and NF-:B target genes (Cole et al. 2007). These isolation-related alterations in leukocyte biology might stem from a functional desensitization of the glucocorticoid receptor (GR) in isolated people (Cole 2008), which in turn, is reciprocally related to NF-:B expression, a key factor in regulation of cellular responses to infection, cancer, and inflammation. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of perceived social isolation. Initial genomics analyses tested a relatively small sample and provided preliminary support for this hypothesis. This revised application seeks to extend those initial findings by (1) expanding the range of genomic analyses, (2) identifying the specific aspect of glucocorticoid-mediated transcriptional control driving those effects, (3) determining the plausibility of a causal role for subjective social isolation in predicting transcriptional control in longitudinal studies, and (4) establishing an animal model of subjective social isolation that can provide a platform for experimental studies. Utilizing participants from the Chicago Health, Aging and Social Relations longitudinal study, a population-based sample of middle-aged and older adults, we investigate whether transcriptional alterations occur only in those who show chronically high levels of subjective isolation, or whether similar effects occur even at minimal or variable levels of subjective isolation. Differential expression of GR and/or NF-:B proteins, and/or post-translational modifications of the GR (e.g., GR phosphorylation) will be examined as potential molecular mechanisms of altered glucocorticoid transcriptional control. The plausibility of a causal role for social isolation will be evaluated by examining the extent to which naturally occurring changes in subjective isolation over a two-year period predict changes in transcriptional control. Finally, a non-human primate model will be evaluated by conducting social behavioral assays to distinguish among and determine stability of "sociability" phenotypes in adult male rhesus monkeys, and biological assays will be done to determine relationships between social phenotypes and measures of HPA activity, GR- mediated signal transduction, and genome-wide transcriptional profiles. PUBLIC HEALTH RELEVANCE: Research has repeatedly shown that social isolation increases risk for poor health. We previously found functional genomic differences between individuals high and low in social isolation which could contribute to differences in risk of disease. The proposed research therefore is designed to identify the specific biological mechanisms mediating these genomic effects.