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

• 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
• 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

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.

两者都是外源性的（例如，电离辐射）和内源性（例如，代谢过程）因素已知 每天都会造成相当大的DNA损伤强大的DNA修复机制通常修复损伤 几分钟内，但修复并不完美。每次修复都有可能导致错误的风险， 导致致癌风险增加的DNA突变。最重要的假设是 我们的研究计划是，反复暴露于日常心理压力可能有助于增加 癌症的风险，反复造成DNA损伤。支持心理压力与DNA之间的联系 损伤来自：1）人类相关性研究; 2）动物实验性应激研究; 3） 组织培养研究表明，短暂暴露于应激激素后，DNA损伤增加， 通过特异性神经内分泌受体阻断（例如，与β-肾上腺素能拮抗剂普萘洛尔）。 严重缺乏实验研究来确定人类DNA损伤的增加可以 由心理压力引起，并通过心得安减少。这里描述的研究目标 就是填补我们知识上的空白参与者的多样化样本（50%女性，50%非洲人 美国人）将暴露于受控的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高度有效、广泛有效和广泛使用的应激源。 之前采集的外周血单核细胞（PBMC）中的总DNA损伤（主要研究结局） 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 (the高度验证的彗星测定）使用新开发的彗星芯片系统。参与beta- 肾上腺素能通路将使用创新的“普萘洛尔/TSST组合范式”进行测试，其中一个 随机分配（双盲）的研究组接受单剂量安全有效的β-肾上腺素能 普萘洛尔组（n=80），在TSST前60分钟给予受体拮抗剂，另一组接受 匹配安慰剂（安慰剂组，n=120）。目的1：通过实验检验暴露于 急性心理应激导致人类DNA损伤增加（目标1.1），同时测试 假设这些作用可以通过β-肾上腺素能受体的药理学阻断来降低（Aim 1.2）。目的2：研究血液中儿茶酚胺水平的增加，作为急性心肌梗死效应的介质。 强调DNA损伤（主要假设），以及探索其他潜在的介质（例如，皮质醇）。目的 3：检查关键人口统计学（种族、性别、年龄）和基线生物学变量（抗氧化活性、DNA 修复能力）作为应激诱导的DNA损伤的易感性/弹性因子（调节剂）。 计划中的研究将确定心理压力是人类DNA损伤的原因， 关键支持新的研究领域探索：1）压力诱导的DNA损伤对癌症风险的影响; 2)具体的分子机制负责; 3）更有选择性的新的干预措施，以防止这种影响。