PROJECT SUMMARY/ABSTRACT Candidate: Dr. Shanlee Davis is a Pediatric Endocrinologist with clinical and research experience in infants, children and adolescents with sex chromosome aneuploidies. She aspires to be an international expert in gon- adal and cardiometabolic function in boys with Klinefelter syndrome (XXY). This award will foster the develop- ment of the skills necessary to lead high-quality patient-centered clinical and translational research in this field. Background: XXY is a common genetic condition leading to physical and psychosocial implications through- out the lifespan in 1 out of every 600 males. XXY has been under-recognized, under-diagnosed, and under- studied. Advances in non-invasive prenatal screening have dramatically increased diagnosis rates of XXY, therefore there is an acute need to address the neurodevelopmental and cardiometabolic challenges facing this population. The normal infantile testosterone (T) surge is blunted in XXY due to testicular dysfunction, and a critical unanswered question is the role of T supplementation during infancy. However, there are no prospec- tive studies examining the benefits or side effects of T supplementation in XXY infants. We hypothesize that T treatment will yield positive changes in cardiometabolic and neurodevelopmental outcomes. Research Plan: TESTO: Testosterone Effects on Short-Term Outcomes in Infants with XXY is a randomized controlled cross-over trial of 12 weeks of supplemental T in infants with XXY. 60 infants between 4 and 12 weeks of age will be randomized 1:1 to receive T during the first or second 12 weeks of the study. Body com- position, neurodevelopment, testicular function, and safety will be assessed at 0, 12, and 24 weeks. We will also explore the effect of T on energy pathways using targeted and unbiased metabolomics analyses. Training: To become an independent investigator, Dr. Davis needs additional training and mentorship in both clinical and translational research. The approach to achieving her career development aims will be 1) experien- tial training in design, implementation and completion of the randomized clinical trial TESTO and 2) scholastic exposure through workshops in translational science and completion of a PhD in Clinical Investigation. Environment: The environment for this project is exceptional with a strong academic Section of Pediatric En- docrinology at the University of Colorado and resources of the Colorado CTSI. The eXtraordinarY Kids Clinic, a one-of-a-kind multidisciplinary clinic for children with XXY, and relationships with parent support groups will assure successful recruitment for this study. Mentors with expertise in endocrinology, developmental pediat- rics, neonatology, genetics, metabolomics and clinical investigation are invested in this candidate's future and will be instrumental in supporting her research and career development. Impact: The results of this study will impact the clinical care of infants with XXY, informing and improving neu- rodevelopmental and cardiometabolic outcomes. Dr. Davis will gain invaluable skills in clinical trial methodolo- gy as well as metabolomics sciences, optimally launching an impactful career as a clinical investigator.