Characterization of a Novel Growth and Survival Factor for Human Mast Cells

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Mast cells are important effectors in a wide array of inflammatory disease states. Although increases in the numbers of tissue mast cells are a consistent feature of asthma, arthritis, and fibrotic diseases, there is little known about the mechanisms that accelerate mast cell growth or sustain their survival beyond the constitutive input from stem cell factor (SCF) and its receptor, c-kit. We have preliminarily characterized a potent growth factor for human mast cells that is secreted spontaneously by a human mast cell line. It is functionally distinct from SCF, and renders primary human mast cells resistant to conventional c-kit inhibitors. The goal of this proposal is to isolate and purify the factor, determine its amino acid sequence, and develop the probes and antibodies needed to determine its sites of expression and its relationship to mast cell hyperplasia in a large collectin of bronchial biopsies from human subjects with severe asthma. Given the importance of mast cells and the limited body of knowledge regarding the mechanisms that control their development in humans, these studies have direct translational and therapeutic implications.