Megan Cooper, MD, PhD
Assistant Professor
Department of Pediatrics Rheumatology
Washington University School of Medicine in St. Louis
Title of project: Intestinal epithelial cell turnover in a murine model of STAT3 gain-of-function
(5/01/17 – 4/30/18)
Dr. Cooper is an Assistant Professor in the Department of Pediatrics, Division of Rheumatology. Her funded project will study a group of patients with genetic abnormalities in STAT3 that causes increased STAT3 function and leads to early-onset autoimmune disease. Most of these patients suffer from gastrointestinal disease including inflammation of the intestines and liver. To further investigate how mutations in STAT3 lead to a human disease, her laboratory generated two mouse models with mutations in the murine Stat3 gene corresponding to those found in patients. Preliminary evaluation of the gastrointestinal tract of these mice suggests that they have abnormalities of their small intestines with increased proliferation of epithelial cells. Her work hypothesizes that increased STAT3 function leads to a phenotype similar to that seen with viral infection and type I interferon signaling with increased epithelial cell turnover and that this is a precursor to inflammation of the intestines. The aims of this project are to: 1) Investigate epithelial cell proliferation in a larger group of mice with Stat3 mutations, and 2) Determine if viral infection alters epithelial cell proliferation in mice with Stat3 mutations and induces enteritis. Dr. Cooper will use in vivo mouse models to complete these studies. This anticipate that this project will provide insight into the mechanisms whereby increased STAT3 function causes inflammation of the intestines and liver in patients.
Kathryn Knoop, PhD
Instructor in Medicine
Division of Gastroenterology
Washington University School of Medicine in St. Louis
Title of Project: Gut Mechanism of Neonatal Sepsis
(5/01/15 – 4/30/17)
Dr. Knoop is a Postdoctoral Research Scholar in the Division of Gastroenterology. Her funded project will study will evaluate if the resident gut bacteria transverses the neonatal intestinal epithelium via GAPs and whether this occurs as part of the normal developmental process or whether this results due to loss of factors in the maternal breast milk that normally inhibit GAP formation. Aim 1 will develop a model for LOS and evaluate if maternal factors in the breast milk inhibit bacterial translocation and sepsis by inhibiting GAP formation, and evaluate if replacing the missing maternal factors can prevent sepsis as a potential therapy for LOS. Aim 2 will evaluate the differences in the immune response after infection with pathogens between neonates and infants to better understand why infants are protected from disease despite presence of bacteria in the organs. Completion of these studies will result in understanding how bacterial strains causing LOS cross the intestinal epithelium and what ages are most susceptible to bacterial translocation. By evaluating if supplementation with maternal factors can prevent sepsis, a potential therapy will have been discovered.
Blair Madison, PhD
Assistant Professor
Division of Gastroenterology
Washington University School of Medicine in St. Louis
Title of Project: Dissecting the Combinatorial Roles of Let-7 Target mRNAs in Colorectal Cancer
(5/01/15 – 4/30/17)
Dr. Madison is an Assistant Professor in the Division of Gastroenterology. His funded project will study the role of Let-7 targets in colorectal tumorigenesis. Using mouse models to manipulate Let-7 levels specifically in the intestine epithelium, he has revealed a critical role for tumor suppression by this miRNA family. However, one of the most arduous task of many miRNA studies is determining the relevant targets that are responsible for a given phenotype. Dr. Madison has identified 8 highly up-regulated Let-7 target mRNAs, including suspected proto-oncogenes HMGA2, IGF2BP1, IGF2BP2, and MYCN, along with several transcription factors: PLAGL2, ARID3A, E2F5, and HIF3A. Although these factors likely operate independently, it was found that several of these targets converge on the pro-oncogenic IGF2/miR-483 locus. The goal of this Pilot and Feasibility project is to examine how these targets cooperatively augment intestinal tumorigenesis, with the hypothesis that activation of the IGF2/miR-483 locus is triggered following loss of Let-7 miRNAs. In addition to in vitro cell culture models (enteroids) for investigating cooperation between these targets, Dr. Madison will test the feasibility of a novel conditional transgenic mouse model using a mutant Piggybac transposase.
Samantha Morris, PhD
Assistant Professor
Department of Developmental Biology and Genetics
Washington University School of Medicine in St. Louis
Title of project: Single-cell RNA-seq mapping of an in vitro intestinal regeneration model
(5/01/17 – 4/30/18)
Dr. Morris is an Assistant Professor in the Department of Developmental Biology and Genetics. Her funded project will study the overarching hypothesis that in vitro intestinal organoid models can recapitulate the in vivo microenvironmental cues to fully differentiate iEPs to mature, functional intestine. The innovation of this project is that we will establish a tractable platform to enable the precise charting of intestinal differentiation from an induced progenitor state, with single-cell resolution. This will pave the way for generating an array of gastrointestinal cells for therapy, and in vitro disease modeling.
Guoyan Zhao, PhD
Assistant Professor
Department of Pathology & Immunology
Washington University School of Medicine in St. Louis
Title of project: Characterization of a Novel Gene Associated with Inflammatory Bowel Disease
(5/01/17 – 4/30/18)
Dr. Zhao is an Assistant Professor in the Department of Pathology & Immunology. Her funded project will study the function of IRNG (IBD-related novel gene) and if it is involved in IBD pathogenesis. From preliminary findings, Dr. Zhao hypothesizes that IRNG encodes a secreted protein and functions as a cytokine. The specific aims are: Specific Aim I: Determine IRNG gene expression in different human tissues and in tissues from IBD patients by computational analysis of published RNA-Seq data. Specific Aim II: Test the hypothesis that IRNG encodes a secreted protein. Specific Aim III: Identify cell-intrinsic function of IRNG by comparing gene expression profiles between wild-type cells and Caco-2 cells lack IRNG function with and without virus infection using RNA-seq. The overall goal is that if IRNG is involved in IBD pathogenesis, it would offer a potential novel target for IBD treatment.