Gene regulation and social relationships across the life course in a nonhuman primate model

项目摘要 社会支持和社会融合是发病率和死亡率的最有力的预测因素。 到目前为止已经确定了。这种关系是由于对几种主要死亡原因的易感性增加所致 美国，包括心脏病和癌症等导致老龄化的重大疾病。最新研究 这表明社会关系的特征也可以在基因调控的数据中检测到，这突出了一个 社会关系“潜伏”影响健康的潜在途径。然而，尽管有大量的 有证据表明，社会关系对健康的影响在生命早期就开始了，目前还没有研究与整个生命相关 社会关系的进程轨迹到基因调控的数据，或者使用这些数据来调查为什么一些 个人似乎比其他人更容易受到社会孤立。 这项研究的目标是通过将细粒度的、纵向的社会数据联系起来，来解决这些差距 与对社会经验的分子签名的公正调查的关系。为此，我们将利用 自然动物种群中社会关系和健康的已建立模型，即 肯尼亚的安博塞利生态系统。这一群体已经成为纵向研究的对象长达9年 几代人，揭示了社会孤立预测寿命缩短的方式与 人类。我们建议将从出生到成年的社会关系的年度衡量标准与基因联系起来 在基线和体外挑战后收集的表达和染色质可及性数据 细菌和病毒的模拟物。这一战略将使我们能够调查重要的社会关系类型 大多数情况下，它们对基因调节的影响的时间，以及它们与免疫功能的相关性，是一个主要的 导致衰老期间健康状况发生变化的因素。 利用这些数据，我们将实现三个目标。首先，我们将描述基因调控签名的特征 在整个生命过程中社会关系的变化。我们将调查早期生命的相关角色， 积累的经验和社会关系接近生物样本收集的时间，以及 社会关系数量与质量的相对重要性。第二，我们将评估个人是否 通过识别基因-社会关系，他们对社会环境的敏感度因基因而异 影响基因表达的相互作用。最后，我们将测试与社会关系相关的后果 免疫防御和寿命的基因调控。通过这样做，这项工作将对以下问题提供重要的启示： 社会关系的基因调控签名很可能机械地牵涉到 社会关系和健康，或者相反，作为被动的生物标志物。总而言之，我们的结果将提供 迄今为止，对社会关系的功能性基因组签名的最全面的窗口。通过 因此，他们将解决三个问题，以揭示何时、如何以及对谁的社会关系最重要 对于理解社会环境对人类健康的作用具有突出重要性的问题。

Project Summary Social support and social integration are some of the most robust predictors of morbidity and mortality identified to date. This relationship arises from increased susceptibility to several of the top causes of death in the United States, including major diseases of aging such as heart disease and cancer. Recent studies suggest that a signature of social relationships is also detectable in data on gene regulation, highlighting a potential pathway through which social ties get “under the skin” to influence health. However, despite abundant evidence that the health effects of social relationships begin early in life, no studies have related the full life course trajectory of social relationships to data on gene regulation, or used these data to investigate why some individuals appear more susceptible to social isolation than others. The goal of this study is to address these gaps by linking fine-grained, longitudinal data on social relationships to unbiased surveys of the molecular signature of social experience. To do so, we will leverage an established model for social relationships and health in natural animal populations, the baboons of the Amboseli ecosystem of Kenya. This population has been the subject of longitudinal study for up to 9 generations, revealing that social isolation predicts shortened lifespan in a manner highly analogous to humans. We propose to link annual measures of social relationships, from birth through adulthood, with gene expression and chromatin accessibility data collected both at baseline and following ex vivo challenge with bacterial and viral mimics. This strategy will allow us to investigate the types of social relationships that matter most, the timing of their effects on gene regulation, and their relevance for immune function, a primary contributor to variation in health during aging. Using these data, we will address three aims. First, we will characterize the gene regulatory signature of variation in social relationships across the life course. We will investigate the relative roles of early life, cumulative experience, and social relationships close to the time of biological sample collection, as well as the relative importance of social relationship quantity versus quality. Second, we will assess whether individuals vary in their sensitivity to social environments based on genotype, by identifying gene-social relationship interactions that affect gene expression. Finally, we will test the consequences of social relationship-associated gene regulation for immune defense and lifespan. In doing so, this work will shed important light on whether gene regulatory signatures of social relationships are likely to be mechanistically implicated in the link between social relationships and health, or instead serve as passive biomarkers. Together, our results will provide the most comprehensive window into the functional genomic signature of social relationships available to date. By revealing when, how, and for whom social relationships matter most, they will therefore address three questions of outstanding importance to understanding the role of the social environment in human health.