The goal of the proposed 3-year training program is the development of the applicant's independent research career as an academic gastroenterologist focused on molecular mechanisms in the pathogenesis of Inflammatory Bowel Disease (IBD). The applicant completed residency training in General Pediatrics, clinical fellowship training in Pediatric Gastroenterology and has joined the faculty of the IBD Center at the Children's Hospital of Philadelphia (CHOP) focusing on the care of children afflicted with IBD. The candidate's near-term goals are to develop and refine the essential skills of experimental design, data interpretation, grant writing, and lab management that will be required for a successful transition to a career as an independent physician- scientist. Defining the molecular requirements for post-transcriptional control of gene expression in the development, function, and pathogenesis of chronic inflammation in the gastrointestinal tract will be the core aim of his research program. Dr. Stephen Liebhaber, an international thought leader in post-transcriptional controls of eukaryotic gene expression, will be the scientific mentor for this proposal. In addition, a group of eminent physician-scientists has been assembled to serve on a Scientific Advisory Committee and support the candidate with his career development. The candidate will draw upon their expertise and the outstanding and highly collaborative training environment and resources available at CHOP and the University of Pennsylvania as he advances toward his goal of becoming an academic gastroenterologist and independent scientist. The research goal of this proposal is to determine the role(s) of an abundant family of RNA-binding proteins in gastrointestinal development and the impact of these proteins on the severity and progression of IBD. RNA-binding proteins and their associated post-transcriptional controls play a critical role in inflammatory processes. The poly-C binding proteins, PCBPs, comprise an important family of RNA-binding proteins that can serve as mediators of inflammation. Gene expression of the PCBP's is significantly altered in human Ulcerative Colitis; however, the functional effect of these changes remains unclear. Preliminary studies by the applicant have documented robust PCBP expression in the mouse colon, demonstrated that PCBP's are essential for normal colonic development, and shown that PCBP's impact inflammation severity in an animal model of colitis. These studies also have revealed a remarkable clustering of PCBP2 binding sites within regulatory regions of colonic mRNAs that can be directly linked to IBD-related pathways.
The research Aims will couple the identification of post-transcriptional regulatory networks coordinated by PCBP's (the PCBP `regulon') with mechanistic studies of specific interactions important for gastrointestinal function and immune responses. The experiments will represent the first transcriptome-scale analysis that uncovers dynamic changes in protein-RNA interactions and the functional consequences of these interactions in models of IBD.
The prevalence of Inflammatory Bowel Disease (IBD) is increasing in the US population. Importantly, the cause(s) of this disease remain poorly defined and currently available treatments for IBD remain limited and often associated with significant adverse effects. Efforts to identify genetic pathways and mechanisms that lead to IBD, as are outlined in the current research proposal, may reveal new approaches and targets for future development.
