Elucidating Olfactory-Based Epigenetic Mediation of Social Contexts on Stress Response Across Life Span in Low SES Inner-City Minority Populations

阐明社会背景中基于嗅觉的表观遗传调节对低社会经济地位内城区少数族群整个生命周期压力反应的影响

• 批准号: 10532745
• 负责人: Evaristus A Nwulia
• 金额: $ 65.43万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532745
• 关键词: Ablation; Adult; Affect; African American; African American population; Amygdaloid structure; Animals; Arousal; Base Sequence; Behavior; Behavioral; Binding; Biological; Biological Process; Biology; Brain; Buffers; C-reactive protein; Child Rearing; Childhood; Chronic; Chronic Disease; Chronic stress; Circadian Dysregulation; Confocal Microscopy; Development; Dimensions; Disease; Disparity; Distress; Environmental Exposure; Environmental Impact; Epigenetic Process; Exposure to; Family; Genes; Genome; Glucocorticoid Receptor; Glucocorticoids; Growth; Health; Hippocampus; Hydrocortisone; Immune signaling; Imprisonment; Individual; Intervention; Longevity; Maternal Deprivation; Measures; Mediating; Mediation; Messenger RNA; Metabolic Diseases; MicroRNAs; Microscopy; Minority Groups; Modeling; Modification; Molecular; Morphology; Neighborhoods; Neurites; Neurons; Neurosciences; Pathway interactions; Physiological; Play; Populations at Risk; Post-Traumatic Stress Disorders; Poverty; Predisposition; Promoter Regions; Prospective Studies; Reflex action; Resolution; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Taking; Role; Salivary; Sampling; Severities; Signal Transduction; Sleep; Sleep disturbances; Social Discrimination; Social Environment; Social support; Spirituality; Stress; Structure; Translating; Untranslated RNA; Variant; assault; behavioral response; biological adaptation to stress; childhood adversity; circadian; circadian regulation; cohort; density; design; developmental plasticity; epigenomics; ethnic disparity; experience; genome-wide; heart rate variability; immune activation; immunocytochemistry; indexing; inner city; innovation; low socioeconomic status; nano; negative affect; neurophysiology; novel; olfactory bulb; pediatric trauma; perceived discrimination; perceived stress; prevent; prospective; racial discrimination; racial disparity; resilience; response; social; social adversity; social disparities; social stress; stress disorder; trauma exposure; ultra high resolution; young adult

ABSTRACT There is substantial ethnic and racial inequity in the burden of social adversities across life span, and disparities in several adult chronic diseases can be traced to social inequalities experienced in childhood. Social adversities such as poverty, harsh parenting, neighborhood disorganization, family instability, and parental incarceration are particularly pervasive in inner-city, African American (AA) populations; and can have substantial impact on biological processes that put them at risk for chronic stress disorders (e.g. posttraumatic stress disorder, PTSD) and metabolic diseases. Previously, we observed that olfactory bulb (OB) volumes were substantially reduced in AA adults who developed PTSD following severe childhood adversities, compared to those with similar exposures who did not develop PTSD, which is congruent with animal studies showing that maternal deprivation reduced OB size. Yet how these social exposures become translated into chronic health disorders, is unclear. Epigenetic factors (i.e. modifications to the genome that are not changes in nucleotide sequence) have been posited to play critical roles in mediating the impact of environmental exposures on health, due to their influence on developmental plasticity and long-term functional biology. Our proposed study builds upon our R21 study in inner-city AA populations which revealed that Growth Arrest Specific 5 (GAS5), a non-coding RNA (lncRNA) likely plays an epigenetic role as a decoy, diverting glucocorticoids from binding to glucocorticoid response elements (GRE) in the promoter regions of genes that respond to glucocorticoids and preventing downstream molecular and physiological effects. African Americans with elevated GAS5 levels, had larger OB volumes, lower afternoon cortisol levels and lower sympathetic arousal independent of burden of neighborhood disorder and perceived social stress and racial discrimination. However, our studies also revealed that social connectedness and Daily Spiritual Experience Scale also moderated a broad spectrum of stress responsive behaviors (e.g. perceived stress, affect, sleep disruptions, risk taking, and resilience), thereby providing a strong justification to investigate genome-wide epigenomic mechanisms of response to social adversities. As a result, we propose a 5-year prospective study involving genome-wide noncoding RNA profiling of 300 AA with dimensional differences in childhood social adversities. Our Specific Aims are: (1) conduct baseline microRNA (miRNA), lncRNA and mRNA profiling in olfactory neurons (ON) of AA cohorts to examine associations between noncoding RNA (ncRNA) and childhood social adversities; (2) quantify baseline associations between ncRNA levels, perceived social stress and racial discrimination, social connectedness, spiritual experience scale, and both behavioral and neurophysiologic measures of stress; and (3) investigate mediational roles of ncRNA on the predictive influences of cumulative exposures to neighborhood stress, poverty, social stress, perceived discrimination and other social disadvantages on 12-month trajectory in stress response behaviors. Our overarching hypothesis is that interactions between miRNA and lncRNA will partially mediate effects of these adverse social contexts (e.g. poverty, neighborhood disorganization, family instability, and parental incarceration) on biological processes related to stress response ( e.g. GR signaling, immune signaling, circadian molecular alterations, and elevated sympathetic tone) and stress responsive behaviors (perceived stress, psychiatric, sleep disruptions, risk taking, and resilience). This project is innovative in using non-invasively derived ON to investigate intraneuronal epigenetic mechanisms in a prospective design, and in use of microscopy to explore intraneuronal interactions between glucocorticoids, GR, miRNA and lncRNA at nano-resolution. Results of this study will provide evidence for the role that ncRNA play in mediating the effects social adversities on chronic diseases, highlight epigenomic signature of resilience and produce epigenomic hotspots for treatment intervention.

抽象的 在一生中所承受的社会逆境负担中存在着严重的民族和种族不平等，并且 一些成人慢性疾病的差异可以追溯到儿童时期经历的社会不平等。 社会逆境，如贫困、严厉的养育、邻里解体、家庭不稳定等 父母被监禁在市中心的非裔美国人 (AA) 人群中尤为普遍；并且可以有 对生物过程产生重大影响，使他们面临慢性应激障碍（例如创伤后应激障碍）的风险 应激障碍（PTSD）和代谢疾病。之前，我们观察到嗅球 (OB) 体积 在严重的童年逆境后患上创伤后应激障碍 (PTSD) 的 AA 成年人中，这种情况大大减少， 与那些没有患上创伤后应激障碍（PTSD）的相似暴露者相比，这与动物研究一致 结果表明，孕产妇剥夺会减少产妇的大小。然而，这些社会曝光如何转化为 慢性健康障碍，尚不清楚。表观遗传因素（即不发生变化的基因组修饰） 在核苷酸序列中）已被认为在介导环境影响中发挥关键作用 由于其对发育可塑性和长期功能生物学的影响，暴露对健康的影响。 我们提出的研究建立在我们对 AA 市中心人口进行的 R21 研究的基础上，该研究揭示了增长 Arrest Specific 5 (GAS5) 是一种非编码 RNA (lncRNA)，可能作为诱饵、转移注意力而发挥表观遗传作用 糖皮质激素与基因启动子区域的糖皮质激素反应元件（GRE）结合 对糖皮质激素作出反应并防止下游分子和生理效应。非裔美国人 GAS5 水平升高，OB 量较大，下午皮质醇水平较低，交感神经较低 唤醒独立于邻里混乱的负担以及感知的社会压力和种族歧视。 然而，我们的研究还表明，社交联系和日常精神体验量表也 调节广泛的压力反应行为（例如感知压力、情感、睡眠中断、 风险承担和恢复力），从而为研究全基因组表观基因组提供了强有力的理由 应对社会逆境的机制。因此，我们提出一项为期 5 年的前瞻性研究，涉及 300 个 AA 的全基因组非编码 RNA 分析，在儿童社会逆境中具有维度差异。 我们的具体目标是：(1) 进行嗅觉基线 microRNA (miRNA)、lncRNA 和 mRNA 分析 AA 队列的神经元 (ON) 检查非编码 RNA (ncRNA) 与儿童社交之间的关联 逆境； (2) 量化 ncRNA 水平、感知的社会压力和种族之间的基线关联 歧视、社会联系、精神体验量表以及行为和神经生理学 压力测量； (3) 研究 ncRNA 对累积累积预测影响的中介作用 面临邻里压力、贫困、社会压力、感知到的歧视和其他社会压力 压力反应行为 12 个月轨迹的劣势。我们的总体假设是 miRNA 和 lncRNA 之间的相互作用将部分调节这些不利社会环境的影响（例如， 贫困、邻里解体、家庭不稳定和父母监禁）对生物过程的影响 与应激反应相关（例如 GR 信号、免疫信号、昼夜节律分子改变和升高 交感神经张力）和压力反应行为（感知压力、精神、睡眠中断、冒险、 和复原力）。该项目的创新之处在于使用非侵入性衍生的ON来研究神经元内 前瞻性设计中的表观遗传机制，以及使用显微镜探索神经元内相互作用 糖皮质激素、GR、miRNA 和 lncRNA 之间的纳米分辨率分析。这项研究的结果将提供 ncRNA 在调节社会逆境对慢性疾病的影响方面发挥作用的证据，强调 恢复力的表观基因组特征并产生用于治疗干预的表观基因组热点。