Expression and Modulation of Mast Cell Function in Asthma

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DESCRIPTION (provided by applicant): We hypothesize that mast cells (MCs) can have direct and indirect effects which can significantly enhance the local development of antigen- (Ag-) induced inflammatory responses in the airways, as well as the structural and functional consequences of such processes in the lungs. Specifically, we hypothesize that, in certain mouse models of acute or chronic allergic inflammation involving the lungs, MC activation by both antibody- (Ab-)dependent and Ab-independent mechanisms results in net effects which can contribute significantly to the development and/or enhancement of the inflammation, airway hyperreactivity (AHR) and tissue remodeling associated with these "asthma models", and that many such effects are promoted by MC- associated TNF and can be enhanced by interferon gamma (IFNgamma), acting via IFNgamma receptors (IFNgammaRs) on MCs. We will test these hypotheses by using different protocols that can elicit either acute or chronic models of asthma in mice. We will examine genetically MC-deficient c-kit mutant mice (WBB6F1-KitW/W-v mice and C57BL/6- KitW-sh/W-sh mice) the congenic Kit+/+ wild type (WT) mice and "MC knock-in mice", i.e., c-kit mutant mice which have been selectively engrafted with WT MCs or MCs which express genetically-determined abnormalities in the expression of products which we hypothesize are involved in the activation, modulation or mediation of MC function. By assessing the extent to which key features of these asthma models differ in c-kit mutant MC-deficient and WT mice, we can quantify the c-kit-dependence of the responses. By determining to what extent any abnormalities in the expression of the responses in c-kit mutant mice are "normalized" or otherwise altered when such mice have been selectively engrafted with WT or genetically-manipulated MCs, we can assess the contribution of MCs, as well as individual MC products, including membrane-associated or soluble TNF, IFNgammaR1 or certain G protein-coupled receptors, to the expression of these features of the responses. By understanding better the mechanisms by which MCs can enhance the development of important features of asthma models in mice, and the mechanisms which influence the extent to which MCs can be activated to express their function in these settings, we will broaden the view of the potential roles of MCs in the development and progression of asthma in humans, and perhaps suggest new approaches for the management of this disorder.