The basic research experience of Phase I of the Physician Scientist Award Program is outlined below. This activity, integrated with the didactic component of the program will prepare Dr. Wershil to investigate the role of mast cells in several pathological processes affecting the gastrointestinal tract during Phase II of the program. Mast cells represent important sources of vasoactive amines (histamine and, in murine rodents, serotonin), proteoglycans (e.g. heparin), certain proteases, and products of arachidonic acid oxidation. Because mast cells reside in virtually all vascularized tissues, and because they may be triggered to release or generate their mediators in response to stimulation by a wide variety of signals (IgE and specific antigen, complement fragments, immune complexes, basic peptides, T cell products, direct injury, etc.), mast cells have been implicated or proposed as critical participants in many immune responses and inflammatory reactions. While such processes may affect many organs, a partial list of gastrointestinal conditions in which mast cells have been implicated includes gastroduodenal ulceration induced by stress and other mechanisms, acute anaphylactic (IgE-dependent) enteropathy, enteropathy due to food allergies, inflammatory bowel disease, celiac disease, T cell dependent immune responses to enteric parasites, the gut changes associated with graft-versus host disease, and eosinophilic gastroenteritis. Yet in none of these processes (including even those involving IgE) has it been possible to define whether mast cells are essential for the pathogenesis of the reaction. We therefore wish to use two different varieties of mutant mice that congenitally lack mast cells to investigate directly the specific contributions of tissue mast cells to three conditions in which mast cells have been thought to have an important role: 1) ethanol-induced acute gastric erosion/ulceration; 2) elicitation of acute inflammation in the skin and peritoneal cavity; 3) regulation of interstitial clotting.
