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

描述（由申请人提供）：社会环境对人类健康和福祉有明显而深刻的影响。长期的社会压力和获得社会支持的机会减少预示着一些不利的健康结果，包括心血管疾病和糖尿病。事实上，有证据表明，社会压力与预期寿命本身有关：例如，社会融合不良被估计为死亡率的风险因素，其程度与吸烟和肥胖等常见健康风险相当。然而，尽管对社会压力作为人类健康问题的浓厚兴趣，但将社会压力与其 对人体的影响仍然知之甚少，特别是在基因组水平上。拟议工作的目标是通过调查雌性恒河猴的优势等级如何影响基因组调控来解决这一差距。猕猴的优势地位是人类社会压力的一个很好的模型：猕猴社会群体的自然等级组织的特点是针对较低等级的群体成员的骚扰和威胁的增加，这反映在等级相关的压力生理学。此外，优势等级分配可以通过改变群体成员资格来实验性地强加于该物种。因此，一个人暴露于社会压力也可以被操纵，产生一个实验系统，用于研究社会压力对基因组的影响，该系统可以直接翻译到人类，但在人类本身中，这在实践和伦理上是不可能的。拟议的研究将利用这一系统来研究显性地位和不同的社会压力暴露如何影响外周血免疫细胞的基因表达。这种关系将在四种不同的细胞类型中进行研究，这些细胞类型在免疫系统中发挥独特的作用，以及在日常条件下和对模拟疾病感染的化合物刺激的反应中。该项目还将调查DNA甲基化的贡献，这是一种重要的标志，可以改变DNA的结构而不改变其序列，并已知会对环境背景，社会地位相关的基因表达变异做出反应。重要的是，研究设计将包括研究中期干预，以系统地改变研究中每个个体的优势等级位置。这种方法既允许识别受暴露于社会压力的因果影响的基因， 并且还允许调查个体的社会压力历史是否对基因组具有长期影响，即使在这种压力已经减轻之后。总之，这些努力将说明社会压力如何改变人类社会压力的重要动物模型中的基因表达，包括压力缓解如何抵消先前压力的生理成本 以及压力的增加如何改变个体对疾病的易感性。 公共卫生相关性：社会环境对人类健康和福祉有着明确而深刻的影响，并可能影响疾病易感性和死亡风险本身。该项目使用了一种非人类灵长类动物模型，即恒河猴，来研究社会压力对基因组的影响。该项目的结果将有助于了解社会压力如何影响疾病易感性，以及减轻社会压力是否有助于消除这些影响。

DESCRIPTION (provided by applicant): 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 predictive of a number of adverse health outcomes, including cardiovascular disease and diabetes. Indeed, evidence suggests that social stress is linked to life expectancy itself: poor social integration, for example, has been estimated as a risk factor for mortality on the scale of familiar health risks like smoking and obesity. However, despite keen interest in social stress as a human health concern, the mechanistic relationships linking social stress to its impact on the body are still poorly understood, particularly on the level of the genome. The goal of the proposed work is to address this gap by investigating how dominance rank in female rhesus macaques influences genome regulation. Dominance status in macaques is an excellent model for human social stress: the natural hierarchical organization of macaque social groups is characterized by increased rates of harassment and threats directed towards lower ranking group members, which are reflected in rank-related stress physiology. Additionally, dominance rank assignments can be experimentally imposed in this species by altering group membership. Thus, an individual's exposure to social stress can also be manipulated, yielding an experimental system for investigating the effects of social stress on the genome that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this system to investigate how dominance status and differential exposure to social stress influence gene expression in immune cells in the peripheral blood. This relationship will be investigated in four different cell types that play unique roles i the immune system, as well as under both day-to-day conditions and in response to stimulation by compounds that mimic disease infection. The project will also investigate the contribution of DNA methylation, an important mark that changes the structure of DNA without altering its sequence and that is known to respond to environmental context, to social status- related gene expression variation. Importantly, the study design will include a mid-study intervention to systematically alter the dominance rank positions of each individual in the study. This approach both permits the identification of genes that are causally influenced by exposure to social stress, and also permits investigation of whether an individual's social stress history has a long-term impact on the genome even after this stress has been alleviated. Together, these efforts will illustrate how social stress changes gene expression in an important animal model for human social stress, including how stress mitigation might offset the physiological costs of prior stress and how increased stress may alter individual vulnerability to disease. PUBLIC HEALTH RELEVANCE: The social environment has a clear and profound impact on human health and wellbeing, and can impact disease susceptibility as well as mortality risk itself. This project uses a nonhuman primate model for human social stress, the rhesus macaque, to investigate the impact of social stress on the genome. The results of this project will contribute to understanding how social stress influences disease susceptibility, and whether alleviation of social stress can help eliminate these effects.