HEMATOPOIETIC MAST CELL REGULATORY FACTORS

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Aberrant production of mast cell effectors is implicated in many important diseases including asthma, inflammatory bowel disease and atherosclerosis, to name just a few. Dysfunction of mast cell regulation is best illustrated by the symptoms resulting from mastocytosis. In a related phenomenon, similar symptoms have been observed in animal and clinical trials with the recombinant Stem Cell Factor. While many reports describe mast cells, much of mast cell development remains a mystery. The long term goal of the research in this project is to identify novel factors which function in regulating mast cell development. Our primary interest is in factors which inhibit or suppress mast cell differentiation or maturation, with a lower priority on stimulatory factors. Inhibitory factors would have significant value, for example in reducing the side effects above of therapy with factors such as stem cell factor. There is considerable evidence for novel regulatory factors, and in this light the objective of this phase I project is to develop and characterize the following molecular tools: 1) subtracted specific domain enrichment libraries from mast cell progenitors; 2) expression libraries from cells which produce regulators; 3) phage display libraries from cells which produce regulators. These libraries will be tested in high throughput assays for their effects on mast cell development. Given success in this research, the cloning of these genes will be pursued in phase II of this project.