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.

项目摘要 社会环境对人类健康和福祉产生明显而深远的影响。慢性社交 压力和减少社会支持的机会与衰老的主要疾病密切相关；结果，社会 逆境高度预测预期寿命本身。最近的证据表明，尽管有一些 关系由相关因素（例如吸烟，肥胖和医疗保健获取）来解释 压力源还会直接影响身体机能。确实，动物模型的工作显然有 证明仅社会服从的经验就可以改变免疫系统的功能 通过改变免疫细胞中基因调节的一部分。 拟议的研究的目的是解决从这些发现引起的一个关键问题： 何时以及为谁而言，慢性社会压力对免疫功能的影响最重要？为此，将需要 女性恒河猕猴中的优势等级作为慢性社会压力源暴露的模型 人类。恒河猕猴是人类社会压力的绝佳模型，因为它们自然而然 组织成主导地等级等级，低排名的个人经历了提高的速率 与等级相关的压力的骚扰，减少的社会会员和身体标记。重要的是， 可以在此操纵主导地位分配，因此可以操纵个人对社会压力源的暴露 通过操纵小组成员资格的物种。这样的操作产生了强大的实验模型 调查社会引起的压力的后果 - 这种方法直接转化为人类， 但这在人类本身上实际上是不可能的。 拟议的研究将利用该模型来研究差异如何接触优势 等级诱导的社会压力会导致免疫系统中的基因表达。具体来说，它将使用 一种体外方法，可以有效筛选针对基因表达水平的特定条件社会压力影响 在30个物理相关的环境条件下（例如病原体暴露，类固醇恐怖剂 信号）。它将通过基因调节和抗体的体内测试来完成体外筛选 对影响力疫苗接种的反应，这是一种特别关注可变响应的医疗程序 随着个人的年龄。最后，它将测试年龄，社会行为和基因型是否可以用于预测 社会压力源对免疫调节的影响的强度差异，因此 个人最脆弱。拟议的分析将共同提供急需的洞察力 解释个人何时以及为何对同一社会压力源的反应以及为什么不同的因素 这些差异对医疗的潜在后果。因此，项目的结果将有 直接翻译应用以确定我们老龄化人口中最敏感的成员以及 提出量身定制的干预策略。