PROJECT SUMMARY/ABSTRACT Restrictive eating disorders (R-EDs) are among the most lethal psychiatric illnesses and common in adolescence. The proposed K23 resubmission will increase our understanding of the brain barrier in R-EDs and test a novel therapeutic target (estrogen) as a neuroprotective moderator of brain barrier functioning, ultimately leading to improved clinical outcomes in R-EDs. My epidemiological research demonstrates that widespread immune dysregulation is prevalent in R-EDs. Estrogen deficiency is common in R-EDs (~60%) and may drive neuroinflammation in R-EDs due to the neuroprotective effects of estrogen on the brain barrier. It remains unclear whether central nervous system (CNS) inflammation (e.g., neuroinflammation) is present in R- EDs, and whether therapy directed at a novel CNS target has beneficial effects on inflammation in R-EDs This K23-Patient Oriented Research Career Development award application uses an innovate translational neuroscience approach to examine the impact of estrogen deficiency and replacement on inflammation, brain- barrier functioning, and core symptoms of R-EDs. By leveraging an ongoing R01 investigating the clinical utility of 12-weeks of estrogen replacement in hypoestrogenemic females with R-EDs, we will evaluate the influence of estrogen replacement (vs. placebo) on inflammation markers (Aim 1), the brain barrier – measured using non-invasive neuroimaging to characterize volume, perfusion, and brain parenchyma extracellular water (Aim 2), and core eating disorder symptoms (Aim 3). The training aim corresponding to this project will support Dr. Lauren Breithaupt in becoming an independent translational scientist with a program of research examining neuroinflammation in eating disorders to identify novel therapeutic treatment targets. Each aim of the study corresponds to a specific training goal, which will map onto three main areas of competency for Dr. Breithaupt : (1) advanced clinical neuroscience principles, (2) non-invasive imaging of brain barrier functioning, and (3) psychoneuroimmunology. Training goals will be implemented under the guidance of Drs. Kamryn Eddy (primary mentor), Marek Kubicki and Madhusmita Misra (co-mentors), Cynthia Bulik, Marco Loggia, Steven Arnold, David Alsop, Beth Stevens, (scientific advisors), and Diego Pizzagalli (collaborator).