Pulmonary arterial hypertension (PAH) is a rare lung disease characterized by progressive pulmonary vascular obliteration resulting in right ventricular failure and ultimately death. Throughout the last three decades there has been tremendous progress in understanding disease mechanisms that have led to new therapies, however survival remains poor at approximately 8 years after diagnosis for most patients. There have been several recent NIH/NHLBI sponsored workshops on phenotyping patients with PAH and moving accumulating “Omic” data into the clinic to advance precision medicine in PAH, yet there are few centers in where this work is ongoing and training the next generation of researchers in these techniques will be critically important to advancing the field of PAH therapy and pulmonary vascular disease more broadly. Dr. Hemnes is a well- recognized expert in this field and her objective is to use the support of the K24 Midcareer Investigator Award in Patient-Oriented Research to focus on training the next generation of scientists to bring precision medicine approaches to PAH patient therapy. The candidate’s immediate and long-term career objectives are directly in line with the goals of the NIH K24 award, to provide support for protected time for awardees to devote to patient-oriented research and culturally-sensitive mentoring for students, residents, fellows and junior faculty. Specifically, this award will allow her to focus on the development of (1) a patient-oriented research program in pulmonary vascular disease research and (2) a mentoring program to facilitate the career development of new investigators. This award will provide protected time for the candidate to devote specifically to developing mentoring skills in patient-oriented research. Her objective is to recruit and mentor students, residents, fellows and junior faculty for successful clinical research careers in pulmonary vascular disease and to support the career advancement of her current trainees who are fellows and junior faculty members. To expand her patient-oriented research program in PAH, she will combine two lines of study in her research portfolio (1) understanding how insulin resistance in the lipid axis may predispose to PAH or affect outcomes and (2) using Omic techniques to deep phenotype patients with pulmonary vascular disease. The proposal here will build on her funded work to test the hypothesis that Omic signatures in PAH can identify features of resilience to PAH progression and metabolic intervention susceptibility. The specific aims are (1) To compare PAH patients with and without Omic signatures of metabolic dysfunction, define differences in clinical and molecular features and measure relevant outcomes between the two groups, (2) To test and validate Omic predictors of metformin responses in completed and ongoing clinical trials in PAH patients. Completion of these aims will enhance understanding of the pathogenesis of PAH and uncover potentially improv...