Supplement to AG057235: Stress and the Genome: Testing the Impact of Social Effects on Gene Regulation

项目摘要 社会环境对人类健康福祉有着明显而深刻的影响。慢性社交 压力和获得社会支持的机会减少与主要的老龄化疾病密切相关；因此，社会 逆境对预期寿命本身具有很高的预测性。最近的证据表明，虽然其中一些 关系由相关因素解释，如吸烟、肥胖、医疗保健途径、社会 应激源也会直接影响生理功能。事实上，在动物模型中的工作显然已经 证明仅仅是社会从属的经历就可以改变免疫系统的功能，在 部分是通过改变免疫细胞中的基因调节。 拟议研究的目标是解决由这些发现引起的一个关键悬而未决的问题： 什么时候，对谁来说，慢性社会压力对免疫功能的影响是最重要的？要做到这一点，需要 雌性恒河猴作为慢性社会应激源暴露模型的优势 人类。雌性恒河猴是人类社会压力的优秀模型，因为它们天生 组织成支配地位的等级等级，在这种等级等级中，排名较低的个体体验到 骚扰，减少社会联系，以及与职级相关的压力的生理标志。重要的是 支配地位的分配，以及个人在社会压力中的暴露，都可以在这种情况下被操纵 通过操控群组成员身份来保护物种。这样的操作产生了一个强大的实验模型 研究社会压力的后果--这是一种可以直接翻译给人类的方法， 但在人类身上，这实际上是不可能的，在伦理上也是不可能的。 拟议中的研究将利用这一模型来调查不同的优势暴露是如何 等级引起的社会压力会影响免疫系统中的基因表达。具体地说，它将使用 一种有效筛选特定条件社会应激对基因表达水平影响的体外方法 30种与生理相关的环境条件(例如，病原体暴露、类固醇激素 信令)。它将补充体外筛查和体内基因调节和抗体测试 对流感疫苗接种的反应，这是一种特别关注可变反应的医疗程序 随着个体年龄的增长。最后，它将测试年龄、社会行为和基因是否可以用来预测 社会应激源强度的个体差异对免疫调节的影响，因此 个人是最脆弱的。总之，拟议的分析将提供亟需的洞察 解释个体何时以及为什么对相同的社会压力的反应不同的因素，以及 这些差异对医疗的潜在后果。因此，该项目的结果将具有 直接翻译应用程序来识别我们老龄化人口中最易受影响的成员以及 建议采取量身定做的干预策略。

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.