R01MD015391

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

There is substantial ethnic and racial inequity in the burden of social adversities across the 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 a 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.
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 the use of microscopy to explore intraneuronal interactions.

Howard University

TO SUPPORT BASIC, CLINICAL, SOCIAL, AND BEHAVIORAL RESEARCH, PROMOTE RESEARCH INFRASTRUCTURE AND TRAINING, FOSTER EMERGING PROGRAMS, DISSEMINATE INFORMATION, AND REACH OUT TO MINORITY AND OTHER HEALTH DISPARITY COMMUNITIES. THE NATIONAL INSTITUTE ON MINORITY HEALTH AND HEALTH DISPARITIES (NIMHD) HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS: (1) THE CENTERS OF EXCELLENCE PROGRAM PROMOTES RESEARCH TO IMPROVE MINORITY HEALTH AND/OR REDUCE AND ELIMINATE HEALTH DISPARITIES, BUILDS RESEARCH CAPACITY FOR MINORITY HEALTH AND HEALTH DISPARITIES RESEARCH IN ACADEMIC INSTITUTIONS, ENCOURAGES PARTICIPATION OF HEALTH DISPARITY GROUPS AND COMMUNITIES IN BIOMEDICAL AND BEHAVIORAL RESEARCH AND PREVENTION AND INTERVENTION ACTIVITIES, AND BRINGS TOGETHER INVESTIGATORS FROM RELEVANT DISCIPLINES IN A MANNER THAT WILL ENHANCE AND EXTEND THE EFFECTIVENESS OF THEIR RESEARCH, (2) NIMHD RESEARCH ENDOWMENT PROGRAM BUILDS RESEARCH CAPACITY AND INFRASTRUCTURE AT ELIGIBLE NIMHD CENTERS OF EXCELLENCE OR ELIGIBLE SECTION 736 HEALTH PROFESSIONS SCHOOLS (42 U.S.C. 293) TO FACILITATE MINORITY HEALTH AND OTHER HEALTH DISPARITIES RESEARCH TO CLOSE THE DISPARITY GAP IN THE BURDEN OF ILLNESS AND DEATH EXPERIENCED BY RACIAL AND ETHNIC MINORITY AMERICANS AND OTHER HEALTH DISPARITY POPULATIONS, PROMOTES A DIVERSE AND STRONG SCIENTIFIC, TECHNOLOGICAL AND ENGINEERING WORKFORCE, AND EMPHASIZES THE RECRUITMENT AND RETENTION OF UNDERREPRESENTED MINORITIES AND OTHER SOCIO-ECONOMICALLY DISADVANTAGED POPULATIONS IN THE FIELDS OF BIOMEDICAL AND BEHAVIORAL RESEARCH AND OTHER AREAS OF THE SCIENTIFIC WORKFORCE, (3) THE CENTERS OF EXCELLENCE ON ENVIRONMENTAL HEALTH DISPARITIES RESEARCH TO STIMULATE BASIC AND APPLIED RESEARCH ON ENVIRONMENTAL HEALTH DISPARITIES, (4) MINORITY HEALTH AND HEALTH DISPARITIES INTERNATIONAL RESEARCH TRAINING PROGRAM (MHIRT) AWARDS ENABLE U.S. INSTITUTIONS TO TAILOR SHORT-TERM BASIC SCIENCE, BIOMEDICAL AND BEHAVIORAL MENTORED STUDENT INTERNATIONAL RESEARCH TRAINING OPPORTUNITIES TO ADDRESS GLOBAL ISSUES RELATED TO UNDERSTANDING, REDUCING, AND ELIMINATING HEALTH DISPARITIES, (5) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM INCREASES PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, ENCOURAGES SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTERS AND ENCOURAGES PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (6) SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTERS TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, INCREASES PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTERS AND ENCOURAGES PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) HEALTH DISPARITIES RESEARCH PROJECT GRANTS (RPG) SUPPORT INNOVATIVE PROJECTS TO ENHANCE OUR UNDERSTANDING OF BIOLOGICAL MECHANISMS, SOCIAL, BEHAVIORAL, AND HEALTH SERVICES THAT CAN DIRECTLY AND DEMONSTRABLY CONTRIBUTE TO THE IMPROVEMENT IN MINORITY HEALTH AND THE ELIMINATION OF HEALTH DISPARITIES WHICH INCLUDES THE (8) RESEARCH CENTERS IN MINORITY INSTITUTIONS (RCMI) BUILD CAPACITY FOR BASIC BIOMEDICAL AND/OR BEHAVIORAL RESEARCH, CLINICAL AND TRANSLATIONAL RESEARCH (RCTR) AND A NETWORK (RCTN) BY FOCUSING ON INSTITUTIONAL RESOURCE DEVELOPMENT, SUCH AS SUPPORTING CORE RESEARCH FACILITIES AND STAFF, PURCHASING ADVANCED INSTRUMENTATION, AND LABORATORY RENOVATIONS/ALTERATIONS (9) CLINICAL RESEARCH EDUCATION AND CAREER DEVELOPMENT (CRECD) AWARDS PROVIDE DIDACTIC TRAINING AND MENTORED CLINICAL RESEARCH EXPERIENCES TO DEVELOP INDEPENDENT RESEARCHERS WHO CAN LEAD CLINICAL RESEARCH STUDIES, ESPECIALLY THOSE ADDRESSING HEALTH DISPARITIES, (10) PATHWAY TO INDEPENDENCE AWARDS (K99/R00) TO INCREASE AND MAINTAIN A STRONG COHORT OF NEW AND TALENTED, NIH-SUPPORTED, INDEPENDENT INVESTIGATORS. (11) NIH RESEARCH CONFERENCE GRANT AND NIH RESEARCH CONFERENCE COOPERATIVE AGREEMENT PROGRAMS SUPPORT HIGH-QUALITY CONFERENCES THAT ARE RELEVANT TO THE MINORITY HEALTH AND HEALTH DISPARITIES, (12) TRANSDISCIPLINARY COLLABORATIVE CENTERS FOR HEALTH DISPARITIES RESEARCH COMPRISE REGIONAL COALITIONS OF ACADEMIC INSTITUTIONS, COMMUNITY ORGANIZATIONS, SERVICE PROVIDERS AND SYSTEMS, GOVERNMENT AGENCIES AND OTHER STAKEHOLDERS CONDUCTING COORDINATED RESEARCH, IMPLEMENTATION AND DISSEMINATION ACTIVITIES THAT TRANSCEND CUSTOMARY APPROACHES AND SILO ORGANIZATIONAL STRUCTURES TO ADDRESS CRITICAL QUESTIONS AT MULTIPLE LEVELS IN INNOVATIVE WAYS FOCUSED ON PRIORITY RESEARCH AREAS IN MINORITY HEALTH AND HEALTH DISPARITIES, (13) RUTH L. KIRSCHSTEIN NRSA INDIVIDUAL PREDOCTORAL FELLOWSHIP

93.307 - Minority Health and Health Disparities Research

National Institute for Minority Health and Health Disparities (NIMHD) [HHS - NIH]

District Of Columbia United States

State-Wide

Social Epigenomics Research Focused on Minority Health and Health Disparities (R01-Clinical Trial Not Allowed) (PAR-19-372)

Amendment Since initial award the total obligations have increased 394% from $652,142 to $3,222,891.