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

摘要 在整个生命周期中，社会逆境的负担存在着严重的民族和种族不平等， 在几种成人慢性病方面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，邻里混乱，家庭不稳定， 父母监禁在市中心，非洲裔美国人（AA）人群中特别普遍;并且可能具有 对生物过程的重大影响，使他们面临慢性应激障碍的风险（例如创伤后 应激障碍，PTSD）和代谢疾病。以前，我们观察到嗅球（OB）体积 在严重的童年逆境后发展为创伤后应激障碍的AA成年人中， 与那些没有患上PTSD的类似暴露者相比，这与动物研究一致 表明母亲的剥夺减少了OB的大小。然而，这些社会曝光如何转化为 慢性疾病，尚不清楚。表观遗传因素（即对基因组的修饰，而不是改变） 在核苷酸序列中）已经被假定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，对健康的暴露。 我们提出的研究建立在我们对市中心AA人群的R21研究的基础上，该研究表明， 阻滞特异性5（GAS 5），一种非编码RNA（lncRNA），可能作为诱饵发挥表观遗传作用， 糖皮质激素与基因启动子区的糖皮质激素反应元件（GRE）结合， 响应糖皮质激素和防止下游分子和生理效应。非裔美国人 GAS 5水平升高，OB体积较大，下午皮质醇水平较低，交感神经水平较低， 唤醒独立于邻里障碍和感知社会压力和种族歧视的负担。 然而，我们的研究也表明，社会联系和日常精神体验量表也 缓和了广泛的压力反应行为（例如，感知压力，影响，睡眠中断， 风险承担，和弹性），从而提供了一个强有力的理由来研究全基因组表观基因组 应对社会逆境的机制。因此，我们建议进行一项为期5年的前瞻性研究， 全基因组非编码RNA分析300个AA与儿童社会逆境的维度差异。 我们的具体目标是：（1）在嗅觉系统中进行microRNA（miRNA）、lncRNA和mRNA的基础分析， 神经元（ON）的AA队列检查之间的关联非编码RNA（ncRNA）和儿童社会 （2）量化ncRNA水平，感知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，行为和神经生理 研究ncRNA对累积应激的预测作用 暴露于邻里压力，贫困，社会压力，感知歧视和其他社会 压力反应行为的12个月轨迹的缺点。我们的首要假设是 miRNA和lncRNA之间的相互作用将部分介导这些不利的社会环境的影响（例如， 贫困、邻里关系混乱、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信号传导、免疫信号传导、昼夜节律分子改变和升高的 交感神经张力）和压力反应行为（感知压力、精神病、睡眠中断、冒险， 的韧性）。本项目创新性地利用非侵入性衍生的ON研究神经元内 在前瞻性设计中的表观遗传机制，并使用显微镜探索神经元内的相互作用 糖皮质激素、GR、miRNA和lncRNA之间的纳米分辨率。这项研究的结果将提供 ncRNA在介导社会逆境对慢性病的影响中所起作用的证据，强调 表观基因组签名的弹性和产生表观基因组热点的治疗干预。

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.