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

基本信息

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
项目类别：
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

项目摘要

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有着明显而深远的影响。慢性社会压力和获得社会支持的机会减少预示着许多不良健康结果，包括心血管疾病和糖尿病。事实上，有证据表明，社会压力与预期寿命本身有关：例如，社会融合不良被认为是导致死亡的一个危险因素，其程度与吸烟和肥胖等常见的健康风险相当。然而，尽管人们对社会压力作为人类健康问题有着浓厚的兴趣，但将社会压力与其健康联系起来的机制关系对身体的影响仍然知之甚少，特别是在基因组水平上。拟议工作的目标是通过研究雌性恒河猴的优势等级如何影响基因组调控来解决这一差距。猕猴的统治地位是人类社会压力的一个很好的模型：猕猴社会群体的自然等级组织的特点是针对较低等级群体成员的骚扰和威胁率增加，这反映在与等级相关的压力生理学中。此外，可以通过改变群体成员身份在该物种中实验性地施加优势等级分配。因此，个体暴露在社会压力下的情况也可以被操纵，从而产生一个用于研究社会压力对基因组影响的实验系统，该系统可以直接转化为人类，但这在人类本身中实际上和伦理上是不可能的。拟议的研究将利用该系统来研究主导地位和社会压力的差异暴露如何影响外周血中免疫细胞的基因表达。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发挥独特的作用，以及在日常条件下和对模拟疾病感染的化合物的刺激做出反应。该项目还将研究 DNA 甲基化的贡献，DNA 甲基化是一种重要的标记，可以在不改变其序列的情况下改变 DNA 结构，并且已知可以对环境背景、社会地位相关的基因表达变化做出反应。重要的是，研究设计将包括研究中期干预，以系统地改变研究中每个人的优势排名位置。这种方法既可以识别受社会压力影响的基因，并且还可以调查个体的社会压力历史是否对基因组产生长期影响，即使在压力缓解后也是如此。这些努力将共同说明社会压力如何改变人类社会压力重要动物模型中的基因表达，包括缓解压力如何抵消先前压力的生理成本以及压力的增加如何改变个体对疾病的脆弱性。公共卫生相关性：社会环境对人类健康和福祉有着明显而深远的影响，并且会影响疾病易感性以及死亡风险本身。该项目使用人类社会压力的非人类灵长类动物模型——恒河猴，来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易感性，以及减轻社会压力是否有助于消除这些影响。