This proposal describes a 5-year plan to develop the principal investigator (PI), Dr. Kelli VanDussen, into an independent academic researcher in the gastrointestinal field. The PI previously acquired training in intestinal development with Dr. Lind Samuelson at the University of Michigan. She is now receiving training in intestinal pathology and mucosal immunology with Dr. Thaddeus Stappenbeck at Washington University for her postdoctoral training. This proposal will provide the PI with formal training in Bioinformatics, Immunology and grant writing as well as technical laboratory training in experimental approaches to study transcriptional regulation and to model intestinal inflammation in the mouse. At the conclusion of the award period, the PI will have acquired the skills and research data necessary to establish and fund a successful academic research career focused on understanding epithelial cell function in intestinal health and disease. Dr. Stappenbeck, Professor of Pathology and Immunology, will provide mentorship to the PI. Dr. Stappenbeck is highly respected in the field for his expertise and scientific rigor in mouse and human intestinal pathology, mouse models and epithelial stem cells. The Stappenbeck lab has ongoing collaborations with other members of the Washington University research community, including Dr. Eugene Oltz (Professor of Pathology and Immunology; expert in transcriptional regulation) and Richard Head (director of Genome Technology Access Center; expert in bioinformatics), who will be part of the PI's scientific advisory committee along with Dr. Nicholas Davidson (Chief, Division of Gastroenterology; expert in lipid trafficking). The PI will take advantage of tis mentorship along with the plethora of basic science, clinical and educational resources available at Washington University to launch her own independent research program. The PI is committed to the following research paradigm: 1) identify disease-associated phenotypes in patient samples, 2) use in vivo mouse models and in vitro systems to understand the mechanistic basis for these phenotypes, and 3) return to the patient in order to advance our understanding of disease and development of therapies. The proposed research is based on the observation that the bile acid nuclear receptor transcription factor FXR was down-regulated in Crohn's patients along with ~400 other epithelial genes in an RNA-seq study of histologically normal intestinal tissue. Although FXR-mediated bile acid signaling has been proposed to be protective in colitis, it is not clear whether FXR signaling in epithelial cells contributes to thi protection. Therefore, the PI is proposing to define the cellular consequences of bile acid signaling through FXR in primary intestinal epithelial cells utilizing novel and available mouse models and an in vitro culture system for non-transformed intestinal epithelial cells. The overall goal of this research is to provide further understanding of the biological drivers of the epithelil cell defects that occur in Crohn's patients and how these defects may be contributing to the chronic nature of this disease.
This career development award will contribute to the scientific and career development of the principal investigator, who is very passionate about performing research that advances our understanding of Crohn's disease and identifying new therapeutic approaches to benefit this patient population. The proposed research will determine the mechanisms by which two environment-sensing transcriptional regulators, FXR and PXR, contribute to the protective function of the epithelial cells that line the intestine. Epithelial cll function is thought to be defective in Crohn's disease patients, thus contributing to the chronic nature of this inflammatory disease
