The candidate's long term goal is to be an independent, funded, surgeon scientist with an immediate goal of developing her basic science and research skills through this K08 program. This application is designed to meet those goals through basic science coursework, hands on laboratory experience, including learning of new research techniques, participation in relevant seminars, manuscript and grant preparation and interactions with other scientists both at the candidate's institution and nationally. The candidate has enlisted the help of two excellent mentors and an advisory committee to guide and evaluate the candidate's progress. This proposal is an extension of work the candidate performed as a research fellow and also the candidate's current work. Successful completion of this project will include an R01 application. Inflammatory bowel disease has been associated with alterations in the tight junction and increases in intestinal permeability. Ulcerative colitis, one of the inflammatory bowel diseases, can be cured by proctocolectomy with ileal pouch anal anastomosis. Pouchitis is the most common complication following surgery, affecting up to 50% of patients. Our preliminary data shows there is a loss of tight junction proteins in the small intestine and colon in ulcerative colitis. The only gene that has been linked to increased susceptibility in inflammatory bowel disease is a mutation in NOD2. Our group has shown that patients with ulcerative colitis and a NOD2 mutation have an increased risk of pouchitis and that they have a much greater loss of tight junction proteins in the inflamed intestine than those patients without a mutation. The overall hypothesis of this K08 project is that alterations in the tight junction complex contribute to the pathophysiology of pouchitis. This will be investigated in an animal model, cell culture model, and in patients. This proposal aims to 1) elucidate the mechanism by which the TJ complex is altered in a rat model of pouchitis; 2) investigate the role of NOD2 in the alterations in the TJ complex in cultured epithelial cells; and 3) to determine whether the increased rate of pouchitis seen in patients with NOD2 mutations who undergo IPAA is associated with alterations in the tight junction complex. ? ? ?
| Poritz, Lisa S; Harris 3rd, Leonard R; Kelly, Ashley A et al. (2011) Increase in the tight junction protein claudin-1 in intestinal inflammation. Dig Dis Sci 56:2802-9 |
