REGULATION AND FUNCTION OF MAST CELL SECRETED PROTEINASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mast cells are orchestrators of tissue immune responses to innate and adaptive challenge. Stimulation of mast cells results in the release of diverse pro-inflammatory mediators, including a class of secreted proteinases. These proteinases are central to the tissue remodeling that is a feature of physiological, and pathological, inflammatroy responses. The long-term objective of the current proposal is to understand the signaling pathways that control pro-inflammatory responses in mast cells. From this understanding, we hope to identify novel targets for intervention in the progression of inflammatory diseases. We will address three specific aims. As described above, mast cells respond to various pro-inflammatory stimuli, including IgE-mediated and innate immunological challenges, as well as to secretagogues and neurotransmitters. These diverse activation mechanisms for mast cells have one key commonality; all involve the sustained elevation of intracellular free-calcium levels. In fact, calcium mobilization using ionophore compounds is sufficient to induce mast cell activation in the absence of other stimuli. The calcium channels that permit this sustained calcium influx are important targets for therapeutic modulation of mast cell responses, but remain undefined at the molecular level. Immunological stimuli appear to induce a highly selective, store-operated calcium conductance. However, several other activating stimuli for mast cells cause the activation of NSCC, which may be encoded by members of the TRP family. The PI¿s laboratory has screened rodent and human mast cells for the representation of TRP channel mRNA and protein. Mast cells contain TRPV2 protein, which as not been described to respond to lipid ligands. TRPV4 message, but not protein, has been detected in mast cells, and the diverse activation mechanisms for this channel may encompass cannabinoids. The mast cells that we have examined do not contain TRPV1, but do express the cannabinoid-sensitive TRPA1 channel. The experiments that we now propose will aim to dissect the regulation, and function, of TRPA1 in mast cells.