ABSTRACT Dr. Annesa Flentje is Associate Professor in Community Health Systems and Department of Psychiatry and Behavioral Sciences at the University of California, San Francisco. She mentors early career researchers in sexual and gender minority (SGM, non-heterosexual and transgender or gender non-binary people, respectively) health, focusing on substance use, minority stress, and epigenomic markers of substance use. SGM people have greater substance use when compared to their cisgender, heterosexual counterparts. The greater rates of substance use are attributed to minority stress exposure (unique stress burden due to discrimination and stigma among SGM people), and substance use increases in the presence of minority stress. Further, unique molecular profiles of both substance use and minority stress have been observed in sexual minority men living with HIV, suggesting that alterations in the epigenome may serve as biological markers for substance use. Unfortunately, research to date is limited because these models have not explicitly compared people living with HIV (PLWH) and people living without HIV (PLWoH). Further, SGM people have unique hormonal exposures that have been unaccounted for in research investigating substance use and potential epigenetic biomarkers for substance use and these hormonal exposures may also be related to alterations in the epigenome. This project will expand Dr. Flentje’s research program to integrate hormonal exposures and HIV status, to be able to identify epigenomic markers of substance use in the presence of endogenous and exogenous hormone exposures comparing PLWH to PLWoH. To support expansion of her research, Dr. Flentje will receive additional training in HIV, hormone exposures, dominance analysis, and epigenetic bioinformatics analysis. This K24 will support Dr. Flentje in mentoring patient-oriented researchers in SGM health who will leverage survey and epigenetic data from existing cohort studies: The PRIDE Study, the MACS/WIHS Combined Cohort Study, and the All of Us Research Program to 1) understand key minority stress predictors of substance use among SGM people and compare the relative strength of these predictors between PLWH and PLWoH; 2) identify endogenous and exogenous hormonal predictors of substance use among SGM people and determine differences in the relative strength of these predictors among PLWH and PLWoH; and 3) derive minority stress, substance use, and hormonal phenotypes among SGM people, identify epigenetic markers of these phenotypes, and identify differences in these epigenetic markers between PLWH and PLWoH. This K24 will support mentorship of early career researchers in SGM health focusing on substance use, HIV, hormonal biology, epigenomics, and minority stress. It will also expand Dr. Flentje’s mentorship skills to integrate structures to support mentees in navigating financial challenges, loan repayment applications, family building, and emotional hardships. As substance use r...