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: 10204868
• 负责人: Luis Bruno Barreiro
• 金额: $ 32.08万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204868
• 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; Human; Illicit Drugs; Immune; Immune response; Immune system; 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; Personal Satisfaction; Physiological; Physiology; 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 Gradients; 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; health care availability; healthy aging; hormonal signals; immune function; immune system function; immunoregulation; in vivo; in vivo evaluation; influenza virus vaccine; insight; inter-individual variation; long term memory; low socioeconomic status; member; mortality risk; nonhuman primate; pathogen exposure; predictive modeling; response; social; social integration; social stress; social stressor; steroid hormone; 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.

项目总结

项目成果

The Immunology of Stress and the Impact of Inflammation on the Brain and Behavior.

• DOI: 10.1192/bja.2020.82
• 发表时间: 2021-05
• 期刊: BJPsych advances
• 影响因子: 1.3
• 作者: Ravi M;Miller AH;Michopoulos V
• 通讯作者: Michopoulos V

The contribution of natural selection to present-day susceptibility to chronic inflammatory and autoimmune disease.

• DOI: 10.1016/j.coi.2014.09.008
• 发表时间: 2014-12
• 期刊: CURRENT OPINION IN IMMUNOLOGY
• 影响因子: 7
• 作者: Brinkworth, Jessica F.;Barreiro, Luis B.
• 通讯作者: Barreiro, Luis B.