The long term objective of this project is to understand to what extent, and by what mechanisms, mast cells (MCs) can influence the expression of many of the clinically important features of chronic inflammatory or immune responses. These features, that can occur in association with diverse adaptive or pathological responses, include the recruitment of leukocytes, the development of tissue fibrosis, the formation of blood vessels, and modulation of the proliferation of those cells that normally reside in the affected tissues, such as epithelial cells, fibroblasts, vascular endothelial cells, and the MC itself. In previous funding periods of this project, we have: 1) identified the MC as a potential source of TNF-a, IL6, MIP-la TGF-B, VPF/VEGF, and several other cytokines, chemokines and growth factors that can contribute to the local expression of inflammatory responses, and 2) developed new model systems for identifying and characterizing the specific roles of MCs during biological responses in vivo, including genetically MC-deficient Kit W/KitW-v mice that have been selectively repaired of their MC deficiency by the long-term adoptive transfer of immature MCs derived in vitro either from the bone marrow cells of the congenic normal (+/+) mice or from other populations of normal or genetically-altered hematopoietic or embryonic stem (ES) cells. We now propose to define in much greater detail the spectrum of protein products that can be secreted by MCs, to characterize mechanisms that can regulate the global or differential secretion of these products by this cell type, and to define the extent to which MCs and their secreted products contribute to the development of certain important features of persistent inflammatory or immune responses. Specifically, we wish to evaluate the hypothesis that the production of cytokines, chemokines and growth factors by MCs represents an important, and perhaps therapeutically accessible, link between the acute and chronic phases of many inflammatory or immune responses. We will: 1) further define the spectrum of cytokines, chemokines and growth factors that can be produced by human and mouse MCs and characterize how the production and release of these cytokines by MCs can be differentially regulated by immunological and non-immunological mechanisms; and 2) characterize certain specific roles of MCs and MC-derived cytokines, chemokines and growth factors in vivo, by analyzing representative inflammatory and immune responses that are associated with leukocyte infiltration and chronic tissue changes, such as epithelial proliferation, fibrosis and/or angiogenesis.
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