application) A research program will be undertaken by the applicant, Richard J Farrell MD, in the Division of Gastroenterology at the Beth Israel Deaconess Medical Center (BIDMC). Dr. Farrell has had substantial basic and clinical research exposure during his Gastroenterology fellowships in Dublin and Boston, during which he showed impressive productivity and commitment to an academic career in patient orientated research. Dr Ciaran P. Kelly, Associate Physician in the Division of Gastroenterology, BIDMC, and Dr J Thomas LaMont, Chief of Gastroenterology at BIDMC will serve as mentors. Despite the impressive strides that have been made in the diagnosis and management of inflammatory bowel disease (IBD), as many as 20% of patients with ulcerative colitis (UC) and over one-third of patients with Crohn's disease (CD) have disease which is refractory to routine medical therapy, particularly glucocorticoids. This frequently results in multiple hospital admissions as well as the need for surgery. The Multidrug Resistance gene (MDR-1) encodes a cell membrane based drug efflux pump (Pp-170) which actively transports MDR substrates, including glucocorticoids and other immunosuppressants used to manage IBD, out of target cells thereby lowering their intracellular concentration to subtherapeutic levels. The long term goal of this project is to determine whether inhibition of MDR function influences the response of IBD patients to glucocorticoids and other immunosuppressive therapy. The underlying hypothesis for this application is that glucocorticoid-refractory IBD is directly related to overexpression of MDR.
The specific aims of this project are; 1) To determine whether the level of human peripheral blood lymphocyte (PBL) MDR expression is independent of disease activity and is an important determinant of the response of IBD patients to glucocorticoids; 2) To determine whether the level of MDR expression significantly influences intracellular PBL glucocorticoid levels and function in IBD patients; and 3) To determine whether the level of constitutive PBL MDR expression is genetically determined. In addition to the research component the applicant will undertake a Masters in Public Health at Harvard School of Public Health. This will include formal research training in 1) Research ethics, 2) Clinical epidemiology, 3) Biostatistics 4) Clinical trials, and 5) Statistical Principles in Medical Research. The very substantial research, educational, and clinical resources of the Harvard Digestive Diseases Center, Harvard School of Public Health and the BIDMC Gastroenterology Division will be committed to the applicant to ensure successful attainment of the goals of this award.
|Farrell, R J; Menconi, M J; Keates, A C et al. (2002) P-glycoprotein-170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes. Aliment Pharmacol Ther 16:1021-31|