PROJECT ABSTRACT Substance use (SU) negatively affects the risk, management, progression, and outcomes of chronic disease and contributes to socioeconomic and racial/ethnic health disparities. Although linkages between SU and chronic disease are well documented, biopsychosocial mechanisms underlying these linkages are poorly understood. Prospective, longitudinal studies that investigate links between SU and chronic disease are needed to inform the development of targeted prevention and intervention efforts. In Phase I of this Center of Biomedical Research Excellence (COBRE), titled Center for Addiction and Disease Risk Exacerbation (CADRE), we made considerable progress toward establishing a multidisciplinary research center of excellence that will be sustainable in this important area. With support from our Administrative and Clinical Laboratory Cores, we provided 11 early stage investigators (ESI) with research funding and career development to support their transition to research independence. Our CADRE team published 612 peer- reviewed articles, 147 of which were directly CADRE-supported, and 4 (of 6) of our initial cohort of Project Leaders (PL) have obtained R01s. In Phase II of the CADRE, we propose to continue to support ESIs leading thematically and technically linked studies. Our three initial Phase II PLs will (1) examine effects of alternative nicotine delivery products on smoking, obesity, and relevant clinical outcomes among people with obesity who smoke (Murphy); (2) investigate the impact of cannabis use and social determinants of health on maternal mental health in pregnant individuals, specifically focusing on people of color (Gunn); and (3) investigate the intergenerational effects of parental alcohol use on child externalizing disorders, a predictor of health problems over the life course (Micalizzi). CADRE PLs and Pilot Project Leaders (PPLs) will benefit from mentorship by faculty mentors who will provide guidance on research, publication, and grantwriting. As in Phase I, the Administrative Core will continue to provide organizational structure and state-of-the-art mentoring; administer the Pilot Projects Program; support diversity and health disparities work; and lead evaluation of all RPs and center components. The Clinical Laboratory Core will continue to provide research infrastructure and resources to the PLs and PPLs, thereby enhancing investigator productivity and promoting research rigor and reproducibility. New to Phase II is a Recruitment, Engagement, and Community Health (REACH) Core that will provide direct support for local, face-to-face and digital recruitment, to help CADRE ESIs meet their enrollment and inclusion goals. Through innovative and interdisciplinary research, conducted across multiple levels of analysis and focused on related questions using common resources and learning experiences, the CADRE will not only contribute new knowledge, but will continue to serve as the nexus and path toward independen...