The high affinity IgE receptor FcepsilonRI is central to asthma, a chronic disease characterized by airway inflammation and hyperresponsiveness to contractile stimuli that promote airway constriction and wheezing. A newly recognized addition to the repertoire of FcepsilonRI-mediated signaling systems is the activation of sphingosine kinase (SPHK) leading to the generation of the novel sphingolipid mediator, sphingosine-1-phosphate (SPP) from sphingosine. SPP secretion is significantly elevated in the airways of asthmatics after segmental antigen challenge, adding this sphingolipid to the variety of mediators that are released during an allergic reaction. ? ? Mast cells are known to be the main effector cells in the elicitation of the IgE-mediated allergic response. In this proposal, we will determine the role of SF2 and its receptors and examine the hypothesis that SPHK is pivotal to the activation of signaling cascades initiated at the FcepsilonRI in mast cells by modulating the balance of the counteracting sphingolipid metabolites, sphingosine and SPP. Hence, enforced expression of different isoforms of SPHK, resulting in SPP generation (and secretion) and reduction of sphingosine levels should enhance mast cell activation and conversely, decreased SPP formation and increased sphingosine due to inhibition of specific isoforms of SPHK, either by genetic manipulations to specifically block their endogenous expression, dominant negative mutants or pharmacologically, should inhibit mast cell activation and prevent downstream events, such as degranulation, secretion of allergic mediators and induction of cytokines and chemokines. ? ? We will also examine a new mechanistic concept for cross communication between FcepsilonRI and GPCRs, whereby IgE triggering stimulates SPHK resulting in increased formation and secretion of SPP, which in turn transactivates the mast cell GPCRs for SPP, EDG-5 and/or EDG-1, leading to amplification of downstream signals important for mast cell activation. ? ? Our central hypothesis states that SPP is an important mediator released by mast cells to regulate resident airway cell function. Hence, we will also examine the role of SPP and its receptors in modulation of human airway smooth muscle cell contraction and proliferation, processes that promote bronchoconstriction and airways remodeling, critically important in the pathobiology of asthma.Increased understanding of cellular pathways regulated by SPHKs, SPP, and its receptors which culminate in asthmatic responses, may help in the development of novel therapeutic strategies aimed specifically at the potent sphingolipid mediator SPP.
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