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

补充：压力和基因组：测试社会效应对基因调控的影响

• 批准号: 9926548
• 负责人: Luis Bruno Barreiro
• 金额: $ 8.89万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926548
• 关键词: Adaptive Immune System; Address; Administrative Supplement; Affect; African American; Age; Aging; American; Animal Model; Applications Grants; Award; Bacterial Antigens; Bacterial Infections; Behavioral; Biological Markers; Cells; Chronic; Cities; Collaborations; Communicable Diseases; Complement; Cryopreservation; Data; Disadvantaged; Disease; Disease susceptibility; Endotoxins; Environment; Environmental Monitoring; Exhibits; Exposure to; Female; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genome; Genomics; Genotype; Goals; Health; Heterogeneity; Human; Immune; Immune response; Immunization; In Vitro; Incidence; Individual; Inequality; Inflammation; Knowledge; Life; Link; Lipopolysaccharides; Longevity; Macaca; Macaca mulatta; Masks; Measures; Mediator of activation protein; Modeling; Neighborhoods; Outcome; Parents; Participant; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Poverty; Predisposition; Prevalence; Regulator Genes; Research; Risk; Risk Behaviors; Role; Sampling; Sampling Studies; Shapes; Social Environment; Social status; Social support; Socioeconomic Status; Source; Stress; Study Subject; Study models; Surveys; Testing; Translating; Trauma; United States; Variant; Viral Antigens; Work; burden of illness; comparative; direct application; environmental stressor; experimental study; genome-wide; health care availability; health difference; health disparity; human population study; immune function; in vivo; in vivo evaluation; influenza virus vaccine; insight; inter-individual variation; low socioeconomic status; nonhuman primate; parent grant; pathogen; predicting response; predictive modeling; racial and ethnic; response; sex; social; social integration; social stress; socioeconomic disadvantage; socioeconomics; stressor; study population; urban area

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.

项目摘要 疾病的发病率、流行率和负担在人类内部和人类之间分布不均， 人口。这种异质性部分是由于在社会逆境中暴露的差异，这反过来又是 社会经济地位、获得社会支持的机会和早期生活不利因素的差异形成了模式。的确， 动物模型的实验研究表明，即使没有差异， 在卫生保健获取或健康风险行为，可以增加疾病的易感性和缩短寿命。他们 研究还表明，社会劣势会增加炎症相关基因的表达， 改变对细菌和病毒抗原的全基因组免疫反应。 这项研究的目的是调查这些发现对人类的可翻译性 通过研究健康背景下社会劣势对免疫基因调控的影响， 差距。具体而言，拟议的研究将描述社会经济地位， 过去的创伤，和外周血单核细胞（PBMC）的基因表达的样本收集的 底特律邻里健康研究（DNHS），底特律城市人口代表性研究。DNHS 样本是这项工作的理想选择，因为它补充了有关个人和 社区水平的社会经济劣势，并且对于此类研究而言，冷冻保存的PBMC用于 研究参与者的代表性子样本。这些样本正是用于慢性 社会压力和免疫基因调控，从而最大限度地提高可比性， 动物模型的发现。值得注意的是，以前在恒河猴中的研究表明，低剂量的 社会地位对基因调节作用在免疫攻击后被夸大。这些观察表明， 社会不利地位在形成对病原体的反应方面特别重要。然而，虽然影响 基因型、年龄和性别对免疫刺激的全基因组基因表达反应的影响 研究表明，人们对慢性社会压力在人类中的作用知之甚少。 这项拟议中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。 在基线和暴露于DNHS后，来自DNHS样品的冷冻保存的PBMC中的表达 细菌内毒素脂多糖它还将调查社会逆境的相对贡献， 遗传祖先在塑造免疫反应。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，这种方法将突出的程度，因果关系的影响， 动物模型中的社会逆境也反映在人类身上。因此，本报告将讨论关于 基因组机制，通过这种机制，社会劣势转化为健康结果， 应用于确定老龄化期间健康差异的来源。