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，不良的心理和身体健康结果与社会孤立密切相关，与感知的社会孤立更密切相关，并且不能用健康行为的差异来解释。最近的研究发现，下丘脑-垂体-肾上腺(HPA)轴对白细胞炎症生物学调节的变化是隔离相关健康风险的潜在机制。报告长期高度主观社交孤立的个人早上皮质醇水平升高(Adams等人。2006)，以及糖皮质激素靶基因和核因子-B靶基因全基因组转录的变化(Cole等人。2007)。这些与隔离相关的白细胞生物学改变可能源于隔离人群中糖皮质激素受体(GR)的功能性脱敏(Cole 2008)，这反过来又与NF-：B表达相互关联，后者是调节细胞对感染、癌症和炎症反应的关键因素。糖皮质激素反应基因转录受损和促炎转录调控通路活性增加为长期感受到高度社会隔离的个人炎症性疾病风险增加提供了一个功能基因组学解释。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。这项修订后的申请旨在通过(1)扩大基因组分析的范围，(2)确定驱动这些效应的糖皮质激素介导的转录控制的特定方面，(3)在纵向研究中确定主观社会隔离在预测转录控制方面的因果作用的可信程度，以及(4)建立主观社会隔离的动物模型，为实验研究提供平台，从而扩展这些初步发现。利用芝加哥健康、老龄化和社会关系纵向研究的参与者，我们调查了转录变化是否只发生在那些表现出长期高主观隔离水平的人中，或者是否即使在最低或可变的主观隔离水平上也发生了类似的影响。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)将被视为糖皮质激素转录调控改变的潜在分子机制。社会隔离的因果作用的合理性将通过检查两年期间主观隔离中自然发生的变化预测转录控制变化的程度来评估。最后，将通过进行社会行为分析来评估非人类灵长类动物模型，以区分和确定成年雄性恒河猴“社会性”表型的稳定性，并将进行生物学分析以确定社会表型与HPA活性、GR介导的信号转导和全基因组转录图谱之间的关系。

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.