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

压力和基因组：测试社会效应对基因调控的影响

• 批准号: 9398561
• 负责人: Luis Bruno Barreiro
• 金额: $ 65.81万
• 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/9398561
• 关键词: Address; Age; Aggressive behavior; Aging; Animal Model; Animals; Antibodies; Antibody Response; Antibody-Producing Cells; Antigens; Area; Award; Cells; Characteristics; Chronic; Competitive Behavior; Complement; Data; Disease; Disease susceptibility; Environmental Monitoring; Ethics; Experimental Models; Exposure to; Female; Funding; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Genotype; Glucocorticoids; Goals; Health; Health Services Accessibility; Healthcare; Human; Illicit Drugs; Immune; Immune response; Immune system; Immunologic Tests; In Vitro; Individual; Inequality; Infection; Inflammation; Influenza; Influenza vaccination; Innate Immune Response; Intervention; Life; Life Expectancy; Link; Lipopolysaccharides; Macaca mulatta; Measures; Mediating; Medical; Memory; Modeling; Molecular; Natural Immunity; Natural Killer Cells; Obesity; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Physiological; Physiology; Plasticizers; Positioning Attribute; Predictive Factor; Predisposition; Procedures; Quantitative Trait Loci; Regulator Genes; Research; Research Design; Risk; Shapes; Signal Pathway; Signal Transduction; Smoking; Social Behavior; Social Environment; Social Hierarchy; Social isolation; Social status; Social support; Stress; Testing; Time; Vaccination; Vaccines; Work; adaptive immunity; affiliative behavior; aging population; behavior influence; cell type; cost; experience; experimental study; healthy aging; immune function; immune system function; immunoregulation; in vivo; influenza virus vaccine; insight; inter-individual variation; long term memory; low socioeconomic status; member; mortality; nonhuman primate; pathogen exposure; predictive modeling; response; social; social integration; social stress; steroid hormone; stressor; study population

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.

项目概要 社会环境对人类健康和福祉有着明显而深远的影响。慢性社交 压力和获得社会支持的机会减少与主要的老龄疾病密切相关；结果，社会 逆境可以高度预测预期寿命本身。最近的证据表明，虽然其中一些 这种关系可以通过相关因素来解释，例如吸烟、肥胖、医疗保健获取、社会 压力源也对生理功能产生直接影响。事实上，动物模型的工作显然已经 证明仅社会从属经历就可以改变免疫系统的功能， 部分是通过改变免疫细胞中的基因调控来实现的。 拟议研究的目标是解决这些发现中出现的一个关键的悬而未决的问题： 慢性社会压力对免疫功能的影响何时、对谁最重要？为此，需要 雌性恒河猴的优势等级作为慢性社会压力源暴露的模型 人类。雌性恒河猴是人类社会压力的优秀模型，因为它们天生就 组织成支配等级层次结构，其中低等级个体的经历率增加 骚扰、社会归属感下降以及与等级相关的压力的生理标志。重要的是， 支配等级的分配，以及个人所面临的社会压力，都可以在这种情况下被操纵 通过操纵群体成员资格来区分物种。这种操作产生了一个强大的实验模型 研究社会引起的压力的后果——一种可直接应用于人类的方法， 但这对于人类本身来说在实践和伦理上都是不可能的。 拟议的研究将利用该模型来研究不同的优势暴露程度 等级引起的社会压力会影响免疫系统中的基因表达。具体来说，它将使用 一种有效筛选特定条件社会压力对基因表达水平影响的体外方法 跨越 30 种生理相关环境条件（例如病原体暴露、类固醇激素 信号）。它将通过基因调控和抗体的体内测试来补充体外筛选 对流感疫苗接种的反应，这是一种需要特别关注可变反应的医疗程序 随着个人年龄的增长。最后，它将测试年龄、社会行为和基因型是否可以用来预测 社会压力源对免疫调节的影响强度存在个体差异，因此 个人是最脆弱的。总之，所提出的分析将为我们提供急需的见解。 解释个体何时以及为何对相同社会压力源的反应不同的因素，以及 这些差异对医疗的潜在影响。因此，该项目的结果将是 直接转化应用来识别我们老龄化人口中最易受影响的成员 建议量身定制的干预策略。