Sylvie Mrug, Ph.D. - US grants

DESCRIPTION (provided by applicant): The purpose of this proposal is to provide Dr. Mrug, the applicant, with new training in substance use research and advanced statistical modeling to develop her career as an independent investigator in the area of adolescent substance use and abuse. The ultimate career goal of the applicant is to develop preventive interventions tailored to specific subgroups of youth. Consistent with this long-term goal, the proposed research program focuses on the role of gender and ethnicity in initiation of substance use in preadolescent and early adolescent populations. Specifically, we seek to 1) describe gender and ethnic differences in preadolescent and early adolescent use of alcohol, tobacco, marijuana, and inhalants;2) examine specific parenting practices as mediators of these gender and ethnic differences;3) identify the impact of neighborhood context on parenting and substance use in preadolescence and early adolescence;and 4) examine whether early initiation of substance use represents higher risk for future substance-related and Functional outcomes in specific gender and ethnic subgroups. This research will provide important insights into the role of gender and ethnicity in early substance use and provide useful information for developing tailored preventive interventions for girls and boys of different ethnicities. The K01 award would provide the applicant with the skills and mentoring necessary to carry out the proposed research and allow her to fully focus on developing the research program. Proposed training activities include a structured 4-year program of individual mentoring, coursework, and supervised research under the direction of senior mentors in the areas of adolescent substance use (Dr. Windle), advanced statistical methods (Dr. Roth), and contextual influences on adolescent risk behavior (Dr. Bolland), as well as additional training in the responsible conduct of research. To accomplish the specific aims of this proposal, Dr. Mrug will conduct secondary data analyses of two data sets (Healthy Passages and Birmingham Youth Violence Study) and collect follow-up data on participants in the Birmingham Youth Violence Study. In addition to publication and conference presentation of empirical findings, Dr. Mrug will write and submit an independent research grant (R01) in later stages of this award.

DESCRIPTION (provided by applicant): Compared to Non-Hispanic Whites, Black Americans carry a disproportionate burden of social risk factors for poor mental health, such as living in violent urban environments and experiencing economic deprivation and discrimination. Despite these risks, Black Americans have lower lifetime prevalence of depressive and anxiety disorders than Whites. The reasons for Black Americans' resilience to these mental health disorders are unknown. This proposal aims to examine cumulative adversity and subsequent diminished neurobiological stress response as a possible explanation of Black Americans' resilience to anxiety and depression. It also aims to investigate the neural mechanisms underlying this resilience. These aims will be accomplished by conducting research interviews with 1,306 young adults (age 20-21; 60% Black, 40% White; 50% female) from an existing community sample who have been previously assessed three times during childhood and adolescence. These research interviews will provide information on adversity experienced by the participants, categorical diagnoses and dimensional measures of internalizing distress, and physiological indicators of reactivity to stress. Neural bases of stress response will be evaluated with functional magnetic resonance imaging (fMRI) for a subset of 120 Black and 120 White participants from the larger study. This study is innovative because it proposes to test a novel mechanism explaining the resilience of Black Americans to depression and anxiety, incorporates both categorical and dimensional measures of internalizing problems, and examines the role of physiological stress response and regulatory neural circuit in the resilience process. The results will have important implications for our understanding of racial disparities i anxiety and depression, neurobiological mechanisms underlying resilience to stress, and relationships between environmental stress, neural and physiological response, and negative affect. These findings will point to novel ways to diagnose and treat mental health problems in Black and White Americans.

Compared to Whites, Blacks carry a disproportionate burden of chronic disease and early mortality. These health disparities have been linked with high levels of psychosocial stress experienced by Blacks (e.g., poverty, interpersonal violence), but the biological mechanisms linking psychosocial stress with health disparities remain poorly understood. Similarly, the extent to which multi-level protective factors (e.g., from individual, interpersonal, and community domains) mitigate the effects of early life stress on health outcomes and underlying biological mechanisms is unknown. This proposal will investigate the hypothesis that early life stress (before age 20) produces DNA methylation profiles that contribute to health disparities in obesity-related outcomes and are transmitted across generations, but can be mitigated by protective factors from individual, interpersonal, and community domains. To achieve the goals of this project, we will capitalize on an existing longitudinal study, the Birmingham Youth Violence Study, which collected prospective, multi-informant data on a variety of early life stressors and protective factors in over 500 individuals (78% Black, 22% White, 50% female) in Birmingham, Alabama, longitudinally at average ages 11, 13 and 19. This project will conduct a follow up assessment on 400 young adults from this cohort (average age 26) and 200 of their offspring (ages 0 to 5). It will involve a comprehensive evaluation of obesity and related biomarkers (blood pressure, glycated hemoglobin, inflammation markers) in the young adults; assessment of obesity and history of early life stress in the offspring; and collection and analyses of salivary DNA from both the young adults and their offspring. The combined data will be used to 1) identify DNA methylation variations that are associated with early life stress and obesity in young adulthood; 2) identify multi-level protective factors that attenuate the associations of early life stress with DNA methylation and obesity; and 3) characterize the extent to which stress-related DNA methylation patterns transmit across generations and contribute to offspring obesity. The findings of this study will provide novel insights into stress-related epigenetic mechanisms that may explain racial health disparities and their transmission across generations, as well as multi-level protective factors that may interrupt the perpetuation of biologically embedded adversity across generations. Better understanding of these processes may lead to development of epigenetic biomarkers for early diagnosis of disease, ability to identify susceptible individuals at risk for adult disease, and development of novel preventive and curative measures that would reduce health disparities.

PROJECT SUMMARY Compared to Whites, Blacks carry a disproportionate burden of chronic disease and early mortality. These health disparities have been linked with high levels of psychosocial stress experienced by Blacks (e.g., poverty, interpersonal violence, and discrimination), but the biological mechanisms linking psychosocial stress with health disparities across the lifespan remain poorly understood. Similarly, the extent to which multi-level protective factors (e.g., from individual, interpersonal, and community domains) mitigate the effects of early life stress on health outcomes and underlying biological mechanisms is unknown. This proposal will investigate the hypothesis that early life stress produces DNA methylation profiles that contribute to health disparities in early markers of chronic disease across several age groups, and these effects are modified by protective factors from individual, interpersonal, and community domains. To achieve the goals of this project, we will capitalize on an existing longitudinal study, Healthy Passages, which collected prospective, multi-informant data on a variety of early life stressors and protective factors in over 1,000 individuals (65% Black, 35% White, 50% female) in Birmingham, Alabama at ages 11, 13, 16, and 19. The proposed project will conduct a follow up assessment on 800 young adults from this cohort (average age 28) and 400 of their offspring (ages 0 to 5). It will involve a comprehensive evaluation of cardiometabolic indicators associated with later chronic disease (obesity, hypertension, hyperglycemia, and inflammation) in the young adults; assessment of prenatal and postnatal stress and protective factors in the offspring; and analyses of saliva DNA from the young adults at ages 19 and 28, and their offspring. The combination of existing and newly collected data will be used to 1) identify DNA methylation variations that are associated with early life stress and cardiometabolic indicators across three developmental periods ? early childhood, late adolescence, and young adulthood; 2) examine the role of race in stress-related DNA methylation and cardiometabolic indicators across the three developmental periods; and 3) identify multi-level protective factors that modify the effects of early life stress on DNA methylation across the three developmental periods. The findings of this study will provide novel insights into stress-related epigenetic mechanisms that may explain racial health disparities across the lifespan, as well as multi-level protective factors that may interrupt the biological embedding of adversity. Better understanding of the role of epigenetics in health disparities may lead to development of epigenetic biomarkers for early diagnosis of disease, ability to identify susceptible individuals at risk for adult disease, and development of novel preventive and curative measures that would reduce health disparities.