PROJECT SUMMARY Urinary tract infection (UTI) is one of the most common bacterial infections in children and results in significant morbidity and mortality. Established risk factors do not account for all pediatric UTI. Recent evidence suggests obesity may play an important role in UTI susceptibility, but the relationship between obesity and pediatric UTI is not defined. In children, several published studies linking obesity to increased UTI risk are based on small study sizes, limited to young children, hospitalized children, or were performed in countries with lower obesity rates than most Western countries. Thus, a comprehensive evaluation of the effects of childhood obesity on UTI susceptibility, frequency, and severity in ambulatory and hospital settings is warranted. In addition, mechanistic studies are needed to define how obesity alters UTI risk. Preliminary data from our team suggest that obesity increases UTI risk by suppressing host UTI defenses – including the production of cytokines, antimicrobial peptides (AMP), and disrupting the bladder’s urothelial barrier. As a result, this application is designed to address the central hypothesis that obesity has an underappreciated and significant impact on UTI risk, recurrence, and severity by weakening innate host UTI defenses. To address this hypothesis, I designed this application to meet the following objectives: (Aim 1) Define the effect of obesity on the frequency and severity of pediatric UTI. I will access a large pediatric accountable care organization database to define UTI incidence, recurrence, and short- and long- term morbidity across all patient care settings. (Aim 2) Interrogate the impact of obesity on the urinary tract’s innate host UTI defenses. I will use an established biorepository to quantify urinary AMPs, proinflammatory cytokines, and a uroplakin barrier protein. Completion of these studies will define the role of obesity as a UTI risk factor in children, as well as establish mechanisms through which obesity increases UTI susceptibility. This work holds significant promise for crucial insight into pediatric UTI management, prevention, and treatment strategies. It also provides me with an exceptional training opportunity to develop the analytic and laboratory skills required to perform impactful outcomes-based translational research focused on pediatric UTI. .