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: 10551798
• 负责人: Christine Ladd-Acosta
• 金额: $ 61.85万
• 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/10551798
• 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 Pulmonary Disease; Chronology; Critical Care; DNA; DNA Methylation; Data; Data Collection; Detection; Discrimination; Disease; Disease Outcome; Disparity; Education; Effectiveness of Interventions; Epidemiology; Epigenetic Process; Exposure to; Frequencies; Gene Expression; Goals; Health; Hospitalization; Income; Individual; Intervention; Knowledge; Longevity; Low Income Population; Low income; Lung; Measures; Mediation; Medicine; Molecular Target; Morbidity - disease rate; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Population; Prevalence; Prevention; Productivity; Protocols documentation; Quality of life; RNA; Research Personnel; Respiratory Disease; Respiratory Signs and Symptoms; Risk Factors; Role; Sampling; Severities; Smoking History; Social Environment; Social Sciences; Socioeconomic Status; Specimen; Sputum; Stress; Testing; United States; Violence; adverse childhood events; biological adaptation to stress; biomarker performance; burden of illness; community violence; design; effectiveness evaluation; environmental stressor; epigenomics; genome-wide; health disparity; health disparity populations; improved; indexing; insight; inter-individual variation; low socioeconomic status; methylation pattern; mortality; perceived stress; poor health outcome; 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）是美国第四大死亡原因， 发病率，包括生活质量差和呼吸道疾病加重导致住院， mortality.目前还没有针对COPD的疾病缓解药物。低收入人群不成比例 受COPD影响，与收入较高的人相比，健康状况明显较差。我们 研究小组和其他人发现，暴露于社会环境压力源的增加与更糟的情况有关。 COPD呼吸道症状和生活质量与年龄、教育、BMI和吸烟无关 历史然而，迄今为止，减少社会/行为风险因素的战略效率低下。因此，在本发明中， 需要减少疾病负担的补充策略;生物机制，例如表观遗传学， 可以提供一个有希望的替代战略。 强有力的平行证据支持表观遗传参与对社会压力的生物反应 暴露和COPD发病机制。个体基因座和表观遗传衰老途径都有牵连。 我们的初步结果进一步支持DNA甲基化（DNAm;一种表观遗传学数据）与这两种基因相关。 在低收入人群中，COPD结局更差，社会压力暴露增加。尽管如此 没有证据表明，没有研究在社会压力和COPD的背景下严格检查DNAm 结果。因此，这项由环境影响指数主导的提案检验了社会环境压力因素有助于 通过表观遗传机制导致COPD呼吸和生活质量结局恶化，包括在 表观遗传衰老途径和个体（非衰老）基因座。我们利用两项现有的COPD研究， 收集了统一的社会压力源指标，包括整个生命周期、COPD健康结果以及 血液和诱导痰生物样本，暴露和结局的患病率和变异性适当。 在目标1中，我们测试了社会压力对COPD健康影响的加速表观遗传衰老机制 结果。在目标2中，我们测试了一组靶向基因座的DNA甲基化机制（以前与DNA甲基化相关）。 COPD、社会经济地位或社会压力源）。对于每一个目标，血液和诱导痰DNA m将 平行检测，并比较不同标本类型的结果，以进一步了解机制/生物标志物 效用要测试的社会压力暴露包括过去不良的童年经历和最近的暴力， 歧视，和感知压力以及压力的综合指数。待检测的COPD结局 包括COPD对健康和生活质量（通过SGRQ和CAT评分）以及呼吸道症状影响 严重程度（通过mMRC和加重频率）。目的3将目的1-2的DNAm结果与诱导的 痰液基因表达水平，以确定下游功能基因表达的变化。我们的结果可以 提供新的DNA和/或RNA生物靶标，其可以干预以改善COPD 特别是在低收入群体中。