The Lumbee tribe of North Carolina is a state-recognized tribe of approximately 60,000 enrolled members, making it the largest American Indian tribe in the eastern United States and one of the largest tribes in the nation. The tribal homeland for the Lumbee tribe is situated in Robeson County, a rural county in southeastern North Carolina that ranks last among North Carolina’s 100 counties in health outcomes and is adversely impacted by social determinants of health. For the past ten years, tribal leadership has been working with universities and community agencies to better understand the health of tribal members; but to date there has been no intentional effort to develop a comprehensive research infrastructure. Data from the North Carolina Division of Health and Human Services Injury and Violence Prevention Branch indicate that American Indians in North Carolina have the highest rates of substance misuse deaths and emergency room visits of all the racial/ethnic groups in the state. North Carolina’s American Indian population consists of eight recognized tribes, only one of which, the Eastern Band of Cherokee Indians, is federally recognized with access to resources from the Indian Health Services. This proposed 2-year planning initiative, led by the Lumbee Tribe, brings together an internationally recognized community relief organization (CORE), a state agency focused on substance misuse epidemiology and prevention (NC DHHS IVP) and five research organizations with national and international reputation in community-based participatory research, substance misuse prevention research and policy development and implementation (UNC DPOP, UNC IPRC, RTI, WFU, UNCP). Our overall objective is to create the research infrastructure to develop and implement evidence-based, community-informed and culturally-appropriate interventions to address the substance misuse epidemic in the Lumbee tribe. Our team will draw on previous substance misuse programming in the Lumbee community to respond to this epidemic, as well as prior efforts to understand the health challenges in tribal communities, including the Native Pathways to Health and the State and Tribal Injury Data Sharing Summit in 2019. Our Specific Aims include: (1) Development of a Substance Misuse Research and Community Advisory Committees from representatives of the Lumbee community and from our five research organizations, with the goal of developing community-driven action research strategies to understand and address substance misuse; (2) Creation of a Lumbee Substance Misuse Data Dashboard and Storyboard to understand the epidemiology of substance misuse and community impact of substance misuse in the Lumbee tribe and identify key driving factors; (3) Formulation of a research training protocol for Lumbee tribal members and ally representatives to evaluation evidence-based interventions currently implemented in the community and programming needs; (4) Laying the groundwork for an indigenous-informed cultural adaptation of an evidence-based pain management intervention to be pilot-tested among Lumbee patients experiencing chronic pain. At the end of this funding, we anticipate being well positioned to have a strong research infrastructure to understand and address substance misuse disparities in the Lumbee community. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions for the overdose epidemic, including opioid and stimulant use disorders, and the crisis of chronic pain. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction and acute and chronic pain.