Stress and the Genome: Testing the Impact of Social Effects on Gene Regulation

项目摘要 社会环境对人类的健康和福祉有着明显而深刻的影响。慢性社交 压力和获得社会支助的机会减少与主要的老龄化疾病密切相关;因此， 逆境对预期寿命本身有很强的预测性。最近的证据表明，虽然其中一些 相关因素如吸烟、肥胖和医疗保健的获得、社会 应激源也对生理功能有直接影响。事实上，动物模型的研究显然 研究表明，仅仅是社会从属关系的经历就可以改变免疫系统的功能， 一部分是通过改变免疫细胞中的基因调控。 拟议研究的目标是解决从这些发现中产生的一个关键的悬而未决的问题： 慢性社会压力对免疫功能的影响在什么时候、对谁最重要？为此， 雌性恒河猴优势等级作为慢性社会应激暴露的模型 人类雌性恒河猴是人类社会压力的绝佳模型，因为它们天生 组织成统治等级等级，其中低等级的个体经历增加的比率， 骚扰，减少社会联系，以及与等级相关的压力的生理标志。重要的是， 优势等级分配，因此，一个人的暴露于社会压力，可以操纵在这一点上， 通过操纵群体成员来控制物种。这样的操作产生了一个强大的实验模型， 调查社会引发的压力的后果--一种直接适用于人类的方法， 但这在人类身上是不可能的 拟议的研究将利用这一模型来探讨差异暴露于优势如何 等级引起的社会压力会影响免疫系统中的基因表达。具体来说，它将使用 一种有效筛选条件特异性社会应激对基因表达水平影响的体外方法 跨越30种生理相关的环境条件（例如，病原体暴露，类固醇激素 信令）。它将补充体外筛选与基因调控和抗体的体内测试 对流感疫苗接种的反应，一种特别关注可变反应的医疗程序 随着个人年龄的增长。最后，它将测试年龄，社会行为和基因型是否可以用来预测 社会压力对免疫调节的影响强度的个体间差异，因此， 个人最脆弱。总之，拟议的分析将提供急需的洞察力， 解释个体何时以及为何对相同社会压力源的反应不同的因素，以及 这些差异对医疗的潜在影响。因此，该项目的成果将 直接翻译应用，以确定我们老龄化人口中最易感的成员， 提出了量身定制的干预策略。

Project Summary The social environment has a clear and profound impact on human health and well being. Chronic social stress and reduced access to social support are strongly linked to major diseases of aging; as a result, social adversity is highly predictive of life expectancy itself. Recent evidence suggests that, while some of this relationship is explained by correlated factors such as smoking, obesity, and health care access, social stressors also have a direct impact on physiological function. Indeed, work in animal models has clearly demonstrated that the experience of social subordination alone can alter the function of the immune system, in part by altering gene regulation in immune cells. The goal of the proposed research is to address a key outstanding question that arises from these findings: when, and for whom, are chronic social stress effects on immune function most important? To do so, it will take advantage of dominance rank in female rhesus macaques as a model for chronic social stressor exposure in humans. Rhesus macaque females are excellent models for human social stress because they naturally organize into dominance rank hierarchies in which low ranking individuals experience increased rates of harassment, reduced social affiliation, and physiological markers of rank-related stress. Importantly, dominance rank assignments, and thus an individual's exposure to social stressors, can be manipulated in this species by manipulating group membership. Such manipulations yield a powerful experimental model for investigating the consequences of socially induced stress—an approach that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this model to investigate how differential exposure to dominance rank-induced social stress causally influences gene expression in the immune system. Specifically, it will use an in vitro approach to efficiently screen for condition-specific social stress effects on gene expression levels across 30 physiologically relevant environmental conditions (e.g., pathogen exposure, steroid hormone signaling). It will complement the in vitro screen with an in vivo test of the gene regulatory and antibody response to influenza vaccination, a medical procedure in which variable responses are of particular concern as individuals age. Finally, it will test whether age, social behavior, and genotype can be used to predict interindividual variation in the strength of social stressor effects on immune regulation, and hence which individuals are most vulnerable. Together, the proposed analyses will provide much-needed insight into the factors that explain when and why individuals differ in their response to the same social stressors, as well as the potential consequences of these differences for medical treatment. The project's results will therefore have direct translational application to both identifying the most susceptible members of our aging population and suggesting tailored strategies for intervention.