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: 8348248
• 负责人: Luis Bruno Barreiro
• 金额: $ 62.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8348248
• 关键词: Address; Animal Model; B-Lymphocytes; Biological; Blood specimen; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Chronic; Collection; Communities; Cytotoxic T-Lymphocytes; DNA Methylation; DNA Structure; Data; Diabetes Mellitus; Disease; Disease susceptibility; Epigenetic Process; Exposure to; Family; Female; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Goals; Health; Helper-Inducer T-Lymphocyte; Hour; Human; Immune; Immune response; Immune system; Immunity; Individual; Infection; Intervention; Intervention Studies; Investigation; Lead; Life Expectancy; Ligands; Link; Macaca; Macaca mulatta; Measures; Modeling; Nucleic Acid Regulatory Sequences; Obesity; Occupations; Outcome; Peripheral Blood Mononuclear Cell; Physiological; Physiology; Play; Population; Positioning Attribute; Predisposition; RNA; RNA Sequences; Recording of previous events; Regulation; Regulator Genes; Research Design; Resources; Risk; Risk Factors; Role; Smoking; Social Environment; Social Impacts; Social status; Social support; Socioeconomic Status; Stress; Study Subject; System; Testing; Time; Variant; Work; base; bisulfite; cell type; cost; design; disorder risk; genome-wide; improved; interest; member; monocyte; mortality; nonhuman primate; peripheral blood; post intervention; research study; response; social; social group; social integration; social stress

DESCRIPTION (provided by applicant): 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 predictive of a number of adverse health outcomes, including cardiovascular disease and diabetes. Indeed, evidence suggests that social stress is linked to life expectancy itself: poor social integration, for example, has been estimated as a risk factor for mortality on the scale of familiar health risks like smoking and obesity. However, despite keen interest in social stress as a human health concern, the mechanistic relationships linking social stress to its impact on the body are still poorly understood, particularly on the level of the genome. The goal of the proposed work is to address this gap by investigating how dominance rank in female rhesus macaques influences genome regulation. Dominance status in macaques is an excellent model for human social stress: the natural hierarchical organization of macaque social groups is characterized by increased rates of harassment and threats directed towards lower ranking group members, which are reflected in rank-related stress physiology. Additionally, dominance rank assignments can be experimentally imposed in this species by altering group membership. Thus, an individual's exposure to social stress can also be manipulated, yielding an experimental system for investigating the effects of social stress on the genome that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this system to investigate how dominance status and differential exposure to social stress influence gene expression in immune cells in the peripheral blood. This relationship will be investigated in four different cell types that play unique roles i the immune system, as well as under both day-to-day conditions and in response to stimulation by compounds that mimic disease infection. The project will also investigate the contribution of DNA methylation, an important mark that changes the structure of DNA without altering its sequence and that is known to respond to environmental context, to social status- related gene expression variation. Importantly, the study design will include a mid-study intervention to systematically alter the dominance rank positions of each individual in the study. This approach both permits the identification of genes that are causally influenced by exposure to social stress, and also permits investigation of whether an individual's social stress history has a long-term impact on the genome even after this stress has been alleviated. Together, these efforts will illustrate how social stress changes gene expression in an important animal model for human social stress, including how stress mitigation might offset the physiological costs of prior stress and how increased stress may alter individual vulnerability to disease. PUBLIC HEALTH RELEVANCE: The social environment has a clear and profound impact on human health and wellbeing, and can impact disease susceptibility as well as mortality risk itself. This project uses a nonhuman primate model for human social stress, the rhesus macaque, to investigate the impact of social stress on the genome. The results of this project will contribute to understanding how social stress influences disease susceptibility, and whether alleviation of social stress can help eliminate these effects.

描述（由申请人提供）：社会环境对人类健康和福祉产生了明显而深远的影响。慢性社会压力和减少获得社会支持的机会可预测许多不良健康结果，包括心血管疾病和糖尿病。确实，证据表明，社会压力与预期寿命本身有关：例如，在熟悉的健康风险等规模上，诸如吸烟和肥胖等熟悉的健康风险的规模上，估计社会融合不良是死亡的危险因素。但是，尽管人们对社会压力作为人类健康的关注，但机械关系将社会压力与之联系在一起 对身体的影响仍然很少了解，尤其是在基因组水平上。拟议工作的目的是通过研究女性恒河猕猴中的优势等级来解决这一差距。猕猴中的优势地位是人类社会压力的一个极好模型：猕猴的自然等级组织的特征是骚扰率提高和针对较低排名群体成员的威胁，这反映在与等级相关的压力生理中。此外，可以通过改变群体成员身份在该物种中实验施加优势等级分配。因此，也可以操纵个人对社会压力的暴露，从而产生一个实验系统，以调查社会压力对人类直接翻译的基因组的影响，但实际上和道德上在人类本身上是不可能的。拟议的研究将利用该系统来调查周围血液中免疫细胞中基因表达的支配地位状态和差异暴露。这种关系将在四种不同的细胞类型中进行研究，这些细胞类型在免疫系统中以及在日常条件下以及对模仿疾病感染的化合物刺激的响应中扮演了独特的角色。该项目还将研究DNA甲基化的贡献，DNA甲基化的贡献是一个重要的标记，它在不改变其序列的情况下改变了DNA的结构，并且已知会响应环境环境对社会状态与社会状态相关的基因表达变异。重要的是，研究设计将包括中间研究干预措施，以系统地改变研究中每个人的主导地位位置。这种方法都允许鉴定受到社会压力的因果影响的基因， 并且还允许调查个人的社会压力史是否对基因组有长期影响，即使在这种压力得到缓解之后。这些努力将共同说明社会压力如何在人类社会压力的重要动物模型中改变基因表达，包括减轻压力如何抵消先前压力的生理成本 压力增加如何改变个人对疾病的脆弱性。 公共卫生相关性：社会环境对人类健康和福祉产生明显而深远的影响，并可能影响疾病的易感性以及死亡率的风险本身。该项目使用非人类灵长类动物模型，用于人类社会压力，恒河猴，研究社会压力对基因组的影响。该项目的结果将有助于了解社会压力如何影响疾病的易感性，以及缓解社会压力是否可以帮助消除这些影响。