PROJECT SUMMARY . Anorexia nervosa (AN) is a psychiatric illness with the single highest premature mortality rate. Despite this, there are no robust treatment options for adult patients with AN. In addition, more than 70% of patients relapse within 25 years after treatment creating a chronic course with poor quality of life. The lack of effective therapeutics is coupled with the lack of molecular mechanisms of AN. Recent genomic studies have identified a “metabolic axis” in AN, but the exact role for metabolism is unclear. Data from acutely weight-restored women with AN (WR-AN) demonstrate significant differences in their oral glucose tolerance tests (OGTT), lipid profiles, and other metabolism markers compared to age- and weight- matched healthy control women (HC). Of note, OGTT in WR-AN is highly reactive in clearing the hyperglycemic peak to return to homeostasis, suggesting that such a bioenergetic efficiency in handling nutrient stressors may be the basis for relapse in AN. We hypothesized that such systemic differences in metabolism would start with the molecular building blocks to generate metabolic functional differences in cells of WR-AN vs. HC, which may be leveraged for novel therapeutics for relapse prevention. Building on our preliminary data, we will test our hypothesis with 3 research aims: (1) molecular characterization of WR-AN and HC using cellular functional assays and gene expression analysis, (2) characterization of WR-AN during the first year of weight maintenance known for its high relapse rates, and (3) ex vivo high-throughput drug and nutrient screening in cellular models of AN derived from WR-AN. The studies proposed herein will provide the groundwork towards a molecular model of AN and generate a translational pipeline for precision therapeutics aimed at enhancing science and medicine for an illness with dismal outcomes, no treatments, and no molecular mechanisms. The proposed research will be accompanied by 2 years of mentored training in K99, where the principal investigator (PI) Dr. Youngjung Kim, MD, PhD, will obtain systematic training in (T1) advanced data science, (T2) translational science, (T3) comprehensive mastery of clinical trials, (T4) career development, and (T5) responsible conduct or research. Proposed training plan builds directly on the PI’s physician-scientist training with experience in molecular experimentation in models of metabolic disorders, clinical research into the metabolism of AN, and clinical independence as an eating disorder psychiatrist. On this foundation, training will be guided by a star team of mentors, including: primary mentor Dr. Roy Perlis, MD, MSc; co-mentors Drs. Madhusmita Misra, MD, MPH and Kamryn Eddy, PhD; advisors Drs. Maurizio Fava, MD and Tom Hildebrandt, PsyD. With guidance from this exceptional mentoring team, the PI will successfully transition to research independence by R00 and succeed in building and leading her independent translational research program.