Effects of psychological stress on DNA damage and repair in healthy BRCA1+ women

心理压力对健康 BRCA1 女性 DNA 损伤和修复的影响

• 批准号: 9206989
• 负责人: DANA H. BOVBJERG
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-18 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206989
• 关键词: Acute; Address; Age; Area; Attention; BRCA1 Mutation; BRCA1 gene; Biological; Biological Assay; Blood specimen; Catecholamines; Cell physiology; Correlation Studies; DNA; DNA Damage; DNA Maintenance; DNA Repair; Data; Double Strand Break Repair; Exposure to; Gamma Rays; Hormones; Hydrocortisone; Inherited; Lead; Link; Literature; Logistics; Measures; Mediating; Metabolic; Methodology; Molecular; Mutagens; Mutation; Participant; Pathway interactions; Penetrance; Peripheral Blood Mononuclear Cell; Pilot Projects; Population; Process; Psychological Stress; Public Health; Race; Radiation; Recovery; Research; Research Design; Research Support; Risk; Risk Estimate; Sampling Studies; Source; Statistical Data Interpretation; Stress; Susceptibility Gene; Technology; Testing; Trier Social Stress Test; Tumor Suppressor Genes; Vulnerable Populations; Woman; Work; alkalinity; anxiety symptoms; cancer prevention; cancer risk; cofactor; cost effective; epidemiology study; experimental study; innovation; lifetime risk; malignant breast neoplasm; novel strategies; primary outcome; programs; psychobiologic; public health relevance; response

 DESCRIPTION (provided by applicant): The mechanisms by which mutations in BRCA1 result in increased risk of breast cancer are not yet fully understood, but are thought to revolve around deficits in cellular machinery responsible for the maintenance of DNA integrity, including DNA repair functions. In addition to well-known effects on repair of double-strand breaks, mutations in BRCA1 are now recognized to impact multiple processes involved in maintaining DNA integrity. Emerging evidence indicates that psychological stress can also negatively impact DNA integrity through molecular pathways leading to increased ROS levels, as well as reductions in DNA repair capacity. These considerations suggest the central hypothesis of our planned program of research: women with BRCA1 mutations may be particularly susceptible to negative effects of psychological stress on DNA integrity. As a first critical test of that hypothesis we will explore the relationships between psychological stress and DNA damage in two conceptually and logistically interrelated pilot studies (final n=50; 25 BRCA1+, 25 age-, race-matched BRCA1-) to confirm feasibility and explore effect sizes for hypothesized relationships. The first pilot study (Aim 1) will use a cross-sectional correlational study design with one primary outcome: baseline DNA damage levels in peripheral blood mononuclear cells (PBMCs) assessed using an innovative CometChip technology under alkaline conditions, (with damage secondarily characterized by assay of: γ-H2AX, pATM, and DNA 8-OHdG). Statistical analyses will explore the strength of relationships between DNA damage levels and participants' responses on validated measures of psychological stress and related constructs, as well as the contribution of DNA repair capacity assessed by recovery from damage induced by ex vivo gamma radiation. The second pilot study (Aim 2) will use an experimental study design with a primary outcome of DNA damage levels in PBMCs isolated from blood samples collected: before (Baseline, T1), immediately after (Stress, T2), and 75 minutes after (Recovery, T3) exposure of participants to the Trier Social Stress Test (TSST), the most well validated experimental stress paradigm in the psychobiological literature. The concurrent use of both research designs with the same study sample and shared blood samples (Baseline) provides a cost effective way to test our overarching hypothesis with approaches having high internal validity (experimental study) and strong external validity (association study), while also allowing direct comparisons between the results from the two approaches. Aim 1: To statistically examine the relationships between psychological stress levels and DNA damage levels in women with (BRCA1+ Group) and without (BRCA1- Group) BRCA1 mutations. Aim 2: To experimentally investigate the impact of acute psychological stress on levels of DNA damage in women with and without BRCA1 mutations. This R03-supported pilot work will document feasibility and provide effect sizes for study hypotheses that will be used as preliminary data for a comprehensive R01 application. Results have methodological, theoretical, and public health significance for reducing breast cancer risk in BRCA1+ women.

 描述（由适用提供）：BRCA1中突变导致乳腺癌风险增加的机制尚未完全了解，但被认为围绕围绕负责维持DNA完整性的细胞机械定义，包括DNA修复功能。除了众所周知的对双链断裂修复的影响外，BRCA1中的突变还被认为会影响维持DNA完整性所涉及的多个过程。新兴的证据表明，心理压力也会通过分子途径对DNA完整性产生负面影响，导致ROS水平升高以及DNA修复能力的降低。这些考虑因素表明我们计划的研究计划的中心假设：BRCA1突变的女性可能特别容易受到心理压力对DNA完整性的负面影响。作为对该假设的第一个关键检验，我们将探讨两个在概念和逻辑上相互关联的试验研究（最终n = 50; 25 BRCA1+，25岁，竞赛匹配的BRCA1-）中的心理压力和DNA损害之间的关系，以确认可行性并探索假设关系的效应大小。第一项试点研究（AIM 1）将使用一个主要结果使用横截面相关研究设计：外周血单核细胞中的基线DNA损伤水平（PBMC）在酒精线条件下使用创新的Cometchip技术评估，（通过kancetip comethip技术）（通过：通过：γ-H2AX，PATM，PATM，DNA和DNA 8-ohoHDG的损伤次要表征。统计分析将探索DNA损伤水平与参与者对经过验证的心理压力和相关结构的措施的反应之间的关系的强度，以及通过离体伽玛辐射引起的损害恢复的DNA修复能力的贡献。 The second pilot study (Aim 2) will use an experimental study design with a primary outcome of DNA damage levels in PBMCs isolated from blood samples collected: before (Baseline, T1), immediately after (Stress, T2), and 75 minutes after (Recovery, T3) exposure of participants to the Trier Social Stress Test (TSST), the most well validated experimental stress paradigm in the psychobiological literature.同一研究样本和共享血液样本（基线）的同时使用两种研究设计提供了一种具有成本效益的方法来测试我们的总体假设，其内部有效性（实验性研究）和强有力的外部有效性（协会研究）也允许使用，同时也允许 两种方法的结果之间的直接比较。目标1：统计地检查患有（BRCA1+组）女性和没有（BRCA1-组）BRCA1突变的女性的心理压力水平与DNA损伤水平之间的关系。目的2：实验研究急性心理压力对患有和没有BRCA1突变女性DNA损伤水平的影响。这项由R03支持的飞行员工作将记录可行性，并为研究假设提供效果大小，这些假设将用作初步数据 全面的R01应用程序。结果具有减少BRCA1+女性乳腺癌风险的方法论，理论和公共卫生意义。