The long-term objective of this project is to understand the physiological regulation of mast cell (MC) development, survival and function and to define how perturbations of these regulatory pathways may contribute to the changes in MC numbers, phenotype, or secretory activity that have been observed in association with many different diseases. MC's are critical participants in both acute IgE-dependent reactions, such as anaphylaxis, as well as in the late phase reactions which contribute to the pathogenesis of allergic asthma. Moreover, MC numbers and/or phenotype can change dramatically during some immune responses, in association with many diseases characterized by chronic inflammation and tissue remodeling, and in certain neoplastic disorders, suggesting that the size and/or functional characteristics of MC populations can be regulated by factors whose expression is altered during the course of these responses. Recent findings have indicated that interactions between the receptor for stem cell factor (SCFR), encoded by the c-kit gene, and its ligand, SCF, importantly regulate many aspects of MC development and function. For example, SCF can promote the survival, adherence, migration and maturation of cells in the MC lineage, can induce the proliferation of immature or mature MC's, can directly induce MC degranulation and mediator release, and can augment the extent of MC mediator release in cells activated through the high affinity receptor for IgE (FceRI). However, there are many significant gaps in our understanding of how SCF regulates MC development and function. For example, it is not known whether the ability of SCF to alter the intensity of an MC-dependent response in vivo primarily reflects actions on MC's themselves or on other SCFR+ lineages. Nor has it been determined to what extent SCF promotes MC survival by influencing Bcl-2- dependent or -independent pathways. Finally, while it is clear that stimulating MC's with SCF induces many cellular responses, including a change in the cells' phenotypic and functional characteristics, the molecular mechanisms responsible for these effect are very incompletely understand. The applicant therefore proposes to test three hypotheses: 1) that SCF and other factors which regulate MC development can influence the expression of MC-dependent biological responses in at least three ways, by altering MC numbers, phenotype or function; 2) that SCF can suppress MC apoptosis by regulating the expression of Bcl-2 or related molecules and that MC apoptosis can result in a marked reduction in tissue MC numbers without the concomitant induction of a significant inflammatory response; and 3) that the distinct spectrum of biological responses which are induced in MC's stimulated via the FceRI or SCFR reflect, at least in part, the distinct patterns of gene expression which are induced in the activated cells.
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