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

项目摘要 疾病的发病率、流行率和负担在人类内部和在人类之间分布不均 人口。这种异质性在一定程度上是由于暴露在社会逆境中的差异，而这反过来又是 以不同的社会经济地位、获得社会支持的机会和早年的不利条件为模式。的确， 动物模型的实验研究表明，即使在没有差异的情况下，社会逆境本身也是 在获得卫生保健或健康危险行为时，会增加疾病易感性，缩短寿命。他们 还表明，社会劣势既会增加炎症相关基因的表达，也会 改变对细菌和病毒抗原的全基因组免疫反应。 这项拟议的研究的目标是调查这些发现对人类的可译性。 在健康背景下研究社会劣势对免疫基因调节的影响 差距。具体地说，拟议的研究将表征社会经济地位与社会经济地位、 既往创伤和外周血单个核细胞(PBMC)基因表达 底特律社区健康研究(DNHS)，底特律城市人口代表性研究。国土安全部 样本是这项工作的理想选择，因为它得到了关于个人和 社区层面的社会经济劣势，在这类研究中不同寻常的是，将PBMC冷冻保存一年 研究参与者中具有代表性的亚样本。这类样本正是慢性疾病研究中使用的类型。 非人灵长类动物的社会压力和免疫基因调节，从而最大限度地与 动物模型的研究结果。值得注意的是，之前对恒河猴的研究表明，低剂量的 在免疫挑战之后，基因调控的社会地位被夸大了。这样的观察表明 在塑造对病原体的反应方面，社会劣势尤为重要。然而，虽然这些效果 基因型、年龄和性别对全基因组基因表达的免疫刺激反应良好 经过研究，人们对慢性社会压力对人类的作用知之甚少。 这项拟议的研究将通过调查社会劣势模式如何免疫基因来解决这一差距 DNHS样本中冷冻保存的PBMC在基线和暴露于 细菌内毒素脂多糖。它还将调查社会逆境和 在塑造免疫反应方面的遗传祖先。通过将这些数据与使用类似的 在非人类灵长类动物模型中，这种方法将突出显示 动物模型中的社会逆境也反映在人类身上。因此，它将解决有关 社会劣势转化为健康结果的基因组机制，直接 应用于识别老龄化期间健康差距的来源。

Project Summary The incidence, prevalence, and burden of disease are unequally distributed within and across human populations. This heterogeneity is due in part to differences in exposure to social adversity, which is in turn patterned by variation in socioeconomic status, access to social support, and early life disadvantage. Indeed, experimental studies in animal models indicate that social adversity per se, even in the absence of differences in health care access or health risk behaviors, can increase disease susceptibility and shorten lifespan. They have also shown that social disadvantage both increases the expression of inflammation-related genes and alters the genome-wide immune response to bacterial and viral antigens. The goal of the proposed research is to investigate the translatability of these findings to human populations by studying the effects of social disadvantage on immune gene regulation in the context of health disparities. Specifically, the proposed study will characterize the relationship between socioeconomic status, past trauma, and peripheral blood mononuclear cell (PBMC) gene expression in samples collected by the Detroit Neighborhood Health Study (DNHS), a population-representative study of urban Detroit. The DNHS sample is ideal for this work because it is complemented by extensive information on individual and neighborhood-level socioeconomic disadvantage and, unusually for such studies, cryopreserved PBMCs for a representative subsample of study participants. Such samples are precisely the type used in studies of chronic social stress and immune gene regulation in nonhuman primates, thus maximizing comparability against findings from animal models. Notably, previous studies in rhesus macaques have shown that the effects of low social status on gene regulation are exaggerated after immune challenge. Such observations suggest that social disadvantage is particularly important in shaping the response to pathogens. However, while the effects of genotype, age, and sex on the genome-wide gene expression response to immune stimulation are well studied, little is known about the role of chronic social stress in humans. The proposed study will address this gap by investigating how social disadvantage patterns immune gene expression in cryopreserved PBMCs from the DNHS sample, both at baseline and following exposure to the bacterial endotoxin lipopolysaccharide. It will also investigate the relative contribution of social adversity and genetic ancestry in shaping the immune response. By comparing these data to data generated using a similar approach in nonhuman primate models, this approach will highlight the degree to which the causal effects of social adversity in animal models are mirrored in humans. It will therefore address key questions about the genomic mechanisms through which social disadvantage translates into health outcomes, with direct application to identifying the sources of health disparities during aging.