Project Summary/Abstract Necrotizing enterocolitis (NEC) is a severe, often fatal intestinal disease of prematurity. Mortality rates approach 50% if surgery is required to resect necrotic and irreversibly damaged intestinal tissue. Extensive preclinical research supports a central role for deleterious unrestrained inflammation in intestinal injury and destruction of the intestinal epithelium. Despite the insight gained from decades of research, treatment options for infants with NEC are non-specific and often ineffective in the most severe cases. Factors that have impeded the development of novel effective therapies for this disease include an incomplete understanding of disease mechanisms in human infants, a lack of biomarkers, and the fragility of critically ill preterm infants. In addition, NEC is a developmental disease associated with intestinal immaturity, which poses a further challenge in that interruption of these developmental processes can have lifelong consequences. To overcome these obstacles, future NEC research must be patient-focused, innovative, and highly collaborative. I have spent the last 14 years dedicated to studying NEC and the immunologic mechanisms of disease. I created the largest biorepository in the world for NEC, which contains tens of thousands of samples obtained prospectively from premature infants that developed NEC and age-matched control infants. The NEC Biorepository is a multi-institutional collaborative of leading investigators in NEC research from across the country. The development of this biorepository was motivated by an urgent need to study larger patient cohorts and the logistical difficulties of obtaining intestinal samples from critically ill neonates undergoing emergent surgery. In addition, my laboratory is pioneering efforts in biotherapeutic design and implementation for NEC. We recently identified the polyfunctional cytokine interleukin-22 as a potentially powerful new immunotherapy for this disease, and we currently hold a patent for its use in the treatment of NEC. This proposal will utilize the invaluable samples in the NEC Biorepository, our collaborative network, and our extensive expertise in this specialized field to accelerate the growth and development of a new era of NEC research. We will define new mechanisms of immunopathogenesis and employ innovative interventions to interrupt the exaggerated injurious response that leads to NEC. In this effort to reprogram intestinal immunity, we will redefine the paradigms that currently exist in our vague understanding of NEC pathogenesis. This NIDDK Catalyst Award provides our research program with the opportunity to use groundbreaking techniques to answer the elusive questions regarding the central disease mechanisms in NEC. We are determined to cure this devastating disease by interrupting the deleterious inflammatory response that results in intestinal injury in preterm neonates.