The objective of this proposal is to provide the applicant with exemplary biomedical research training in the field of pediatric gastrointestinal disease and to prepare the applicant for a career as an independent research scientist. To achieve this objective, a training regimen within the scope of inflammatory bowel disease (IBD) has been developed, consisting of research aims and substantial training activities. IBD is an intestinal disorder characterized by chronic inflammation, resulting in diarrhea, weight loss, growth failure, rectal bleeding, abscesses, strictures, or fistulas. IBD comprises two disease types, Crohn's disease (CD) and ulcerative colitis (UC), and is one of the most serious diseases affecting the health of children; the peak diagnosis period for both CD and UC occurs during childhood. Recently, several studies have described changes in the expression of microRNAs (miRNAs) in the intestine of adults with IBD, yet the role of miRNAs in the disease process has not been described and virtually nothing is known regarding miRNAs in pediatric IBD. Experiments proposed under this award are designed to 1) identify changes in mucosal miRNA expression in pediatric CD, 2) discover mRNAs targeted by intestinal epithelial miRNAs in vitro and in vivo and 3) determine the role of the miR- 194/192/215 family in perpetuating intestinal inflammation in vivo. High-throughput sequencing will be used throughout to quantify miRNA and mRNA levels. Transgenic mice will be designed to specifically inhibit intestinal miR-194/192/215 activity thereby allowing for the discovery of the miRNA-targeted transcriptome and the role of these miRNAs in potentiating intestinal inflammation. The proposed research and training will occur at The Children's Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (UPENN). The CHOP/UPENN campus provides extraordinary training opportunities for young scientists. An experienced mentoring team has been assembled to guide the scientific activities and to oversee the applicant's acquisition of the professional skills required of an independent scientist. The training plan includes intramural and extramural coursework, training in new methodologies, attendance at national conferences as well as local seminar series, training in the responsible conduct of research, and lectures designed to improve grant writing skills. Overall, the proposed activities will provide the applicant with tools, skills, and discoveries that will serve as the foundation for a successful independent career in gastroenterology research.
Inflammatory bowel disease (IBD) is an intestinal disorder that causes diarrhea, bloody stools, abdominal pain, weight loss, and other potentially disabling symptoms. The goal of this proposal is to determine the role of intestinal microRNAs, a newly discovered type of gene regulator, in children with IBD. The knowledge gained from this study will increase our understanding of IBD and can potentially lead to novel therapies, thereby limiting the delayed maturation and debilitating symptoms in these children.
| Serr, Isabelle; Scherm, Martin G; Zahm, Adam M et al. (2018) A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Sci Transl Med 10: |
| Aoki, Reina; Shoshkes-Carmel, Michal; Gao, Nan et al. (2016) Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell Mol Gastroenterol Hepatol 2:175-188 |
