The role of epigenetics in the adverse effects of social environmental stressors on COPD outcomes

表观遗传学在社会环境压力因素对慢性阻塞性肺病结局的不利影响中的作用

• 批准号: 10052092
• 负责人: Christine Ladd-Acosta
• 金额: $ 58.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-13 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10052092
• 关键词: Acceleration; Address; Adverse effects; Affect; Age; Aging; Algorithms; Behavior Therapy; Behavioral; Biological; Biological Markers; Blood; Body mass index; Cause of Death; Cell physiology; Chronic Obstructive Airway Disease; Chronology; Communities; Critical Care; DNA; DNA Methylation; Data; Data Collection; Detection; Discrimination; Disease; Disease Outcome; Education; Effectiveness of Interventions; Epidemiology; Epigenetic Process; Exposure to; Frequencies; Gene Expression; Goals; Health; Hospitalization; Income; Individual; Intervention; Knowledge; Lead; Longevity; Low Income Population; Low income; Lung; Lung diseases; Measures; Mediation; Medicine; Molecular Target; Morbidity - disease rate; Outcome; Pathogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Prevalence; Protocols documentation; Quality of life; RNA; Research Personnel; Respiratory Signs and Symptoms; Risk Factors; Role; Sampling; Severities; Smoking History; Social Environment; Social Sciences; Socioeconomic Status; Specimen; Sputum; Stress; Testing; Time; United States; Violence; adverse childhood events; biological adaptation to stress; biomarker performance; burden of illness; data curation; design; effectiveness evaluation; environmental stressor; epigenomics; genome-wide; health disparity; health disparity populations; improved; indexing; insight; inter-individual variation; low socioeconomic status; mortality; perceived stress; preventive intervention; respiratory; response; social; social stress; social stressor; stem; stressor; success; treatment strategy

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States with high morbidity, including poor quality of life and respiratory exacerbations leading to hospitalization and increased mortality. There are no disease modifying drugs for COPD. Low-income individuals are disproportionately affected by COPD and have significantly worse health outcomes compared to those with higher income. Our team, and others, found that increased exposure to social environmental stressors is associated with worse COPD respiratory symptoms and quality of life, independent of chronologic age, education, BMI, and smoking history. However, strategies to reduce social/behavioral risk factors have, to date, been inefficient. Thus, complementary strategies to reduce the burden of disease are needed; biologic mechanisms, e.g. epigenetics, that could be intervened upon, could provide a promising alternative strategy. Strong parallel lines of evidence support epigenetic involvement in the biologic response to social stress exposures and for COPD pathogenesis. Both individual loci and the epigenetic aging pathway are implicated. Our preliminary results further support DNA methylation (DNAm; a type of epigenetic data) is related to both worse COPD outcomes and increased social stress exposure, in a low-income population. Despite this evidence, no studies have rigorously examined DNAm in the context of both social stressors and COPD outcomes. Therefore, this ESI-led proposal tests the hypothesis that social environment stressors contribute to worsened COPD respiratory and quality of life outcomes through epigenetic mechanisms, including in the epigenetic aging pathway and at individual (non-aging) loci. We leverage two existing COPD studies that collected unified measures of social stressors, from across the lifespan, COPD health outcomes, as well as blood and induced sputum biosamples with suitable prevalence and variability in exposures and outcomes. In Aim 1, we test for accelerated epigenetic aging mechanisms in social stress effects on COPD health outcomes. In Aim 2, we test for DNA methylation mechanisms at a targeted set of loci (previously associated with COPD, socioeconomic position, or social stressors). For each aim, blood and induced sputum DNAm will be tested in parallel, and results compared across specimen types to further inform mechanism/biomarker utility. Social stress exposures to be tested include past adverse childhood experience and recent violence, discrimination, and perceived stress as well as a composite index of stress. COPD outcomes to be tested include impact of COPD on health and life quality (via SGRQ and CAT score) and respiratory symptom severity (via mMRC and exacerbation frequency). Aim 3 will relate DNAm findings from Aims 1-2 to induced sputum gene expression levels to identify downstream functional gene expression changes. Our results can provide new DNA and/or RNA biologic targets that could be intervened upon to improve COPD outcomes, particularly in low-income groups.

项目摘要 慢性阻塞性肺疾病（COPD）是美国的第四大死亡原因 发病率，包括生活质量差和呼吸系统加重导致住院和增加 死亡。没有针对COPD修改药物的疾病。低收入个人不成比例 与收入较高的人相比，受COPD的影响，健康结果明显较差。我们的 团队和其他人发现，增加对社会环境压力源的暴露量与更糟 COPD呼吸道症状和生活质量，独立于年龄，教育，BMI和吸烟 历史。但是，迄今为止，减少社会/行为风险因素的策略效率低下。因此， 需要减轻疾病负担的互补策略；生物机制，例如表观遗传学， 可以进行干预，可以提供有希望的替代策略。 强大的平行证据线支持表观遗传参与对社会压力的生物学反应 暴露和COPD发病机理。涉及单个基因座和表观遗传衰老途径。 我们的初步结果进一步支持DNA甲基化（DNAM；一种表观遗传数据）与两者有关 在低收入人群中，COPD结局较差，并增加了社会压力。尽管如此 证据，在社会压力源和COPD的背景下，没有严格检查DNAM的研究 结果。因此，这项领导的建议检验了社会环境压力源有贡献的假设 通过表观遗传机制，包括 表观遗传老化途径和单个（非衰老）基因座。我们利用两项现有的COPD研究 从整个生命周期，COPD健康结果以及 血液和诱导的痰液生物样本，其暴露和结局适当流行和变化。 在AIM 1中，我们测试了社会压力对COPD健康的加速表观遗传衰老机制 结果。在AIM 2中，我们在靶向基因座（以前相关的基因座）上测试DNA甲基化机制 具有COPD，社会经济地位或社会压力源）。对于每个目标，血液和诱导的痰液DNAM都会 并行测试，并在样品类型上进行比较，以进一步告知机制/生物标志物 公用事业。要测试的社会压力暴露包括过去的不良童年经历和最近的暴力行为， 歧视，感知的压力以及应力的综合指数。要测试的COPD结果 包括COPD对健康和生活质量的影响（通过SGRQ和CAT评分）和呼吸道症状 严重程度（通过MMRC和恶化频率）。 AIM 3将与AIMS 1-2的DNAN发现相关联 痰液基因表达水平鉴定下游功能基因表达变化。我们的结果可以 提供新的DNA和/或RNA生物学靶标，可以介入以改善COPD 结果，特别是在低收入群体中。