PROJECT SUMMARY The overall goal of this application is to support a NIDDK Mentored Research Scientist Development Award (K01) for the applicant, Dr. Victoria Weis, PhD, at the intersection of epithelial cell biology, pediatric intestinal disease, and novel translational therapeutics to study necrotizing enterocolitis (NEC), a devastating intestinal disease affecting the most fragile premature infants. There are no effective therapies currently available and mortality rates persist at 20-40%. As the population of premature infants at highest risk for NEC continues to rise due to overall improvements in NICU care, an urgent need has emerged to develop innovative clinically translatable therapies to combat this disease. Despite decades of research targeted at uncovering the risk factors and mechanisms for onset of NEC, the field has not progressed to the point of clinically available therapies. We posit that a critical barrier preventing the development of clinically translatable therapeutic candidates is the lack of understanding in the remedial dynamic mechanisms involved in NEC repair and epithelial restitution. Our group has recently shown promising results with the use of perinatal stem cells isolated from placental tissue in facilitating the reparative process through regulation of the inflammatory response and re-establishment of the intestinal stem cell niche and epithelial barrier. We hypothesize that the dual supportive role of placental stem cells on immune modulation and epithelial regeneration will enable us to uncover the dynamic mechanisms responsible for initiating intestinal repair in NEC, to guide further efforts in advanced therapeutic development. The specific aims of this application reflect a rigorous study of the mechanisms and time-course involved in placental stem cell attenuation of NEC to examine: (1) reparative cellular and molecular dynamics in in vivo NEC intestinal damage and (2) direct therapeutic effects specifically on NEC damaged epithelium in vitro with targeted translation into human NEC disease. In addition, a comprehensive career development plan has been developed that supports Dr. Weis?s continued scientific growth and transition into an independent investigator studying pediatric intestinal disease models to identify, characterize, and translate novel therapeutics. An expert multidisciplinary committee across the fields of novel translational stem cell therapy, in vitro organ/disease modeling, advanced imaging and analysis, gastroenterology, and neonatology have been assembled and will provide guidance for Dr. Weis?s career trajectory. This career development plan supplements Dr. Weis?s existing skill-set and expertise in gastrointestinal cell biology and development/characterization of animal disease models with advanced didactic coursework, mentoring in new skills, and laboratory training in in vitro model systems, novel therapeutics, and translational research. Combined with mentoring and advising in other essential skills (e.g. grant writing, budgeting, personnel management), this career development award will ensure successful transition into independence as a uniquely trained investigator in translational aspects of pediatric intestinal diseases, enabling Dr. Weis to make important impacts early in her career as an independent investigator.

K01DK125633

2021-09-03

2026-08-31