West Virginia (WV), the only state located entirely in Appalachia, has the lowest life expectancy in the nation and ranks at or near the bottom in many chronic disease categories. The WV Clinical and Translational Science Institute (WVCTSI) was created in 2012 through the initial Institutional Development Award for Clinical and Translational Research (IDeA-CTR) and successfully renewed in 2017. Over the past 9 years, WVCTSI has cultivated and nurtured a highly collaborative, statewide research infrastructure to address the substantial health disparities in WV. Over the past 4 years, WVCTSI productivity has been superb with 1,325 publications, 951 funding applications, and 688 external funding awards totaling $159.3 MM. The WVCTSI’s overarching goal for the next funding cycle is to serve as a transformational force, leading statewide clinical and translational collaborative research that positively impacts health outcomes in WV. We will achieve this goal through the following specific aims: Specific Aim 1 - Build collaborative, productive research infrastructure across WV that substantively contributes to improving WV health outcomes, Specific Aim 2 - Train and position for success the next generation of clinical and translational scientists, and Specific Aim 3 - Actively engage multiple stakeholders, including rural communities, in research and effectively disseminate research results to rural populations in a manner that facilitates understanding and trust. There are 3 important cross-cutting themes around which our efforts will be focused that include: 1) Rural Health, 2) Diversity, Equity, and Inclusion (engaging not only WV’s rural communities but also WV’s communities of color; equally important is supporting diverse investigators), and 3) the clinician scientists of tomorrow – able to frame the right questions and work to find the answers. Central to attainment of our specific aims is the highly collaborative statewide organization that WVCTSI has developed over the preceding 9 years and that now includes every major healthcare organization and academic medical center in WV, the state health department (WVDHHR), the National Institute for Occupational Safety and Health, and >100 primary care organizations across WV that constitute the WV Practice-Based Research Network. Equally important is the high level of collaboration and commitment among WVCTSI’s cores. Successful completion of our objectives will inform policy, practice, and community changes resulting in improved WV health outcomes.