The Research: The goals of this translational research project are to test the efficacy of clotrimazole (CLT) in the treatment of diarrheal disease. We have previously reported that CLT inhibits intestinal fluid secretion in vitro and in vivo by blocking basolateral membrane K+ channels in enterocytes. We have recently discovered that protease inhibitors (PI's) used in the treatment HIV infected patients elicit a C1-secretory responses in cultured intestinal epithelial cells that is inhibited fully by CLT. Secretory diarrhea can be a dose limiting side effect of PI therapy, and the development of effective anti-secretory therapies would expand the utility of these important anti-therapy, and the development of effective anti-secretory therapies would expand the utility of these important anti-viral agents. In more recent studies, we have found that CLT inhibits the transmigration of neutrophils (PMN's) across cultured intestinal epithelial T84 cell monolayers. PMN transmigration and mucosal ulceration underlie all inflammatory and infectious diarrheas. In the clinical studies proposed, we will test the efficacy of oral CLT therapy in the treatment of the secretory diarrhea found in patients with high output ileostomies and in patients taking the HIV-1 protease inhibitor nelfinavir. In a separate study, we will test the efficacy of topical CLT in patients with distal intestinal inflammation (pouchitis). The Candidate: Dr. Rufo is a fully trained pediatric gastroenterologist who has committed to pursuing a career in academic medicine in the area of translational research. His basic findings have resulted in two first authored publications in The Journal of Clinical Investigation, and established the scientific rationale for clinical trials proposed. Dr. Rufo has been a productive researcher, and has the clear potential to become a creative investigator. We will devote 80% effort to the training program outlined in this grant application. The Environment: Dr. Rufo has been assigned office space within the Gastroenterology Division at Children's Hospital, and will continue to participate in Dr. Wayne Lencer's epithelial cell biology group. In addition, Dr. Rufo will participate in the seminars and research meeting available through the Harvard Digestive Disease Center and the Harvard/MIT scientific communities. Dr. Patricia Hibberd will serve as Dr. Rufo's mentor in clinical research. A panel of well respected individuals (on campus) has been arranged to oversee this research training and career development. To receive formal training in biostatistics, epidemiology, and research ethics, Dr. Rufo will complete a Masters of Medical Sciences degree program at Harvard Medical School.
| Walker, Thomas R; Land, Michelle L; Kartashov, Alex et al. (2007) Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44:414-22 |
| Rufo, Paul A; Lin, Patricia W; Andrade, Adriana et al. (2004) Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling. Am J Physiol Cell Physiol 286:C998-C1008 |
