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

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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.