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.

摘要 在一生中，社会逆境的负担存在着严重的族裔和种族不平等，以及 几种成人慢性病的差异可以追溯到童年经历的社会不平等。 社会逆境，如贫困、严苛的育儿、邻里混乱、家庭不稳定和 父母监禁在市中心的非裔美国人(AA)人群中尤其普遍； 对生物过程产生重大影响，使他们面临慢性应激障碍的风险(例如创伤后 应激障碍、创伤后应激障碍)和代谢性疾病。之前，我们观察到嗅球(OB)体积 在经历了严重的童年逆境后患上创伤后应激障碍的AA成年人中， 与那些没有患上创伤后应激障碍的相似暴露的人相比，这与动物研究是一致的 表明母性剥夺减少了OB的大小。然而，这些社交曝光率如何转化为 慢性健康障碍，目前尚不清楚。表观遗传因素(即对基因组的非改变的修饰 在核苷酸序列中)被认为在调节环境影响方面发挥了关键作用 对健康的影响，因为它们对发育可塑性和长期功能生物学产生影响。 我们建议的研究建立在我们在市中心AA人群中的R21研究的基础上，该研究揭示了增长 5(Gas5)，一个非编码的RNA(LncRNA)可能作为诱饵发挥表观遗传作用，转移 糖皮质激素与糖皮质激素反应元件(GRE)在基因启动子区的结合 对糖皮质激素作出反应，防止下游的分子和生理影响。非洲裔美国人 Gas5水平升高时，OB量较大，下午皮质醇水平较低，交感神经较低 独立于邻里混乱的负担、感知的社会压力和种族歧视的唤醒。 然而，我们的研究也发现，社会连通性和日常精神体验量表也 缓和了广泛的压力反应行为(例如，感知到的压力、情感、睡眠中断、 冒险和韧性)，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，我们建议进行一项为期5年的前瞻性研究，包括 儿童社会逆境中存在维度差异的300个氨基酸的全基因组非编码RNA图谱。 我们的具体目标是：(1)在嗅觉中进行基线microRNA(MiRNA)、lncRNA和mR-NA谱分析 AA队列的神经元(ON)，以检查非编码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 辨别、社会联系、精神体验量表，以及行为和神经生理学 应激措施；以及(3)研究ncRNA在累积压力预测影响中的中介作用。 暴露于邻里压力、贫困、社会压力、感觉到的歧视和其他社会问题 12个月应激反应行为轨迹的不足之处。我们最重要的假设是 MiRNA和lncRNA之间的相互作用将部分中介这些不利社会背景的影响(例如 贫困、邻里混乱、家庭不稳定和父母监禁)对生物过程的影响 与应激反应有关(例如，GR信号、免疫信号、昼夜分子变化和升高 感同身受的语气)和压力反应行为(感觉到的压力、精神病、睡眠中断、冒险、 和韧性)。该项目在使用非侵入性衍生技术研究神经细胞内方面具有创新性。 前瞻性设计中的表观遗传机制，并利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。这项研究的结果将提供 NcRNA在调节社会逆境对慢性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，并产生表观基因组热点用于治疗干预。