Experimental study of stress and DNA damage in humans: Mediators and moderators

人类压力和 DNA 损伤的实验研究：中介者和调节者

基本信息

批准号：
9216858
负责人：
DANA H. BOVBJERG
金额：
$ 31.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-16 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9216858
关键词：
Acute Address Adrenergic Agents Adrenergic beta-Antagonists African American Age Animals Antioxidants Area Biological Blood Catecholamines Cell physiology Cells Cigarette Comet Assay Correlation Studies DNA DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Alteration DNA lesion Data Dose Double-Blind Method Exposure to Glucocorticoids Goals Health Hormones Human Hydrocortisone Individual Intervention Ionizing radiation Knowledge Laboratories Lead Lesion Life Link Mediating Mediator of activation protein Metabolism Modeling Molecular Mutagenesis Mutation Neurosecretory Systems Outcome Study Participant Pathway interactions Peripheral Blood Mononuclear Cell Pharmacology Placebos Predisposition Prevention Process Propranolol Psychological Stress Publishing Race Radiation Randomized Reactive Oxygen Species Recruitment Activity Research Risk Sampling Severities Source Standardization Stress System Testing Time Trier Social Stress Test Woman acute stress aged alkalinity beta-adrenergic receptor biobehavior cancer risk cancer type carcinogenesis daughter cell design experimental study healthy volunteer innovation novel oxidative DNA damage pre-clinical prevent programs receptor repaired resilience sex social stress stressor tissue culture tumorigenesis

项目摘要

Both exogenous (e.g., ionizing radiation) and endogenous (e.g., metabolic processes) factors are known to cause considerable DNA damage on a daily basis. Robust DNA repair mechanisms normally repair damage within minutes, but repair is not perfect. With each repair comes the risk of an error that could result in introduction of a DNA mutation contributing to increased risk of carcinogenesis. The overarching hypothesis of our program of research is that repeated exposures to daily psychological stresses may contribute to increased risk of cancer by repeatedly causing DNA damage. Support for a link between psychological stress and DNA damage comes from: 1) correlational studies in humans; 2) experimental stress studies in animals; and, 3) tissue culture studies demonstrating increased DNA damage after brief exposure to stress hormones, and prevention by specific neuroendocrine receptor blocking (e.g., with the beta-adrenergic antagonist, propranolol). Critically lacking are experimental studies to establish that increases in DNA damage in humans can be caused by psychological stress and reduced by propranolol. The goal of the research described here is to address those gaps in our knowledge. A diverse sample of participants (50% women, 50% African American) will be exposed to a controlled laboratory social stress challenge (Trier Social Stress Test, TSST), which is the most highly validated, broadly effective, and widely used stressor in human biobehavioral research. Total DNA damage (primary study outcome) in peripheral blood mononuclear cells (PBMCs) collected before and after exposure to the TSST will be assessed by single cell gel electrophoresis under alkaline conditions (the highly validated Comet assay) using a newly developed CometChip system. The involvement of beta- adrenergic pathways will be tested using an innovative “Combined Propranolol/TSST Paradigm”, with one study group randomly assigned (double blind) to receive a single dose of a safe and effective beta-adrenergic receptor antagonist 60 minutes prior to the TSST (Propranolol Group, n=80), while another will receive matching placebo (Placebo Group, n=120). Aim 1: To experimentally test the hypothesis that exposure to an acute psychological stress causes increased DNA damage in humans (Aim 1.1), while concurrently testing the hypothesis that these effects can be reduced by pharmacological blockade of beta-adrenergic receptors (Aim 1.2). Aim 2: To investigate increases in blood levels of catecholamines as mediators of the effects of acute stress on DNA damage (primary hypothesis), as well as explore other potential mediators (e.g., cortisol). Aim 3: To examine key demographic (race, sex, age) and baseline biological variables (anti-oxidant activity, DNA repair capacity) as susceptibility/resiliency factors (moderators) of stress-induced DNA damage. The planned research will establish psychological stress as a cause of DNA damage in humans, providing critical support for new areas of research to explore: 1) effects of stress-induced DNA damage on cancer risk; 2) specific molecular mechanisms responsible; 3) more selective novel interventions to prevent such effects.

已知外源性（例如电离辐射）和内源性（例如代谢过程）因素每天都会造成相当大的 DNA 损伤强大的 DNA 修复机制通常会修复损伤。几分钟之内，但修复并不完美，每次修复都会带来可能导致错误的风险。引入导致致癌风险增加的 DNA 突变。我们的研究计划是，反复承受日常心理压力可能会导致反复造成 DNA 损伤而导致癌症的风险支持心理压力与 DNA 之间的联系。损害来自：1）人类相关研究；2）动物实验压力研究；3）组织培养研究表明短暂暴露于应激激素后 DNA 损伤增加，以及通过特定的神经内分泌受体阻断（例如，使用β-肾上腺素能拮抗剂普萘洛尔）来预防。严重缺乏实验研究来证明人类 DNA 损伤的增加可以由心理压力引起并通过普萘洛尔减少此处描述的研究目标。是为了解决我们知识中的这些差距。参与者样本多样化（50% 是女性，50% 是非洲人）。美国）将接受受控实验室社会压力挑战（特里尔社会压力测试，TSST），这是人类生物行为研究中最有效、最有效、最广泛使用的压力源。之前收集的外周血单核细胞 (PBMC) 中的总 DNA 损伤（主要研究结果）暴露于 TSST 后，将在碱性条件下通过单细胞凝胶电泳进行评估（经过高度验证的彗星测定）使用新开发的彗星芯片系统。肾上腺素能途径将使用创新的“普萘洛尔/TSST 组合范例”进行测试，其中一个研究小组随机分配（双盲）接受单剂安全有效的β-肾上腺素能药物 TSST 前 60 分钟接受受体拮抗剂（普萘洛尔组，n=80），而另一个将接受匹配安慰剂（安慰剂组，n=120）目标 1：通过实验检验暴露于安慰剂的假设。急性心理压力会导致人类 DNA 损伤增加（目标 1.1），同时测试假设这些影响可以通过药物阻断 β-肾上腺素受体来减少（目的 1.2) 目标 2：研究血液中儿茶酚胺水平的升高作为急性应激反应的影响因素。 DNA 损伤的压力（主要假设），以及探索其他潜在的介质（例如皮质醇）。 3：检查关键人口统计数据（种族、性别、年龄）和基线生物变量（抗氧化活性、DNA 修复能力）作为压力诱导的 DNA 损伤的易感性/弹性因素（调节剂）。计划中的研究将确定心理压力是人类 DNA 损伤的一个原因，提供为探索新的研究领域提供重要支持：1）压力引起的 DNA 损伤对癌症风险的影响； 2）特定的分子机制；3）更有选择性的新干预措施来防止这种影响。