Ongoing studies by the group of investigators described in this application include projects examining signal transduction mechanisms involved in insulin secretion and insulin action, the biochemical pharmacology of transplanted organ rejection and cyclosporin nephrotoxicity, and the role of lipid mediators in the pathophysiology of inflammatory airway disease. All of these projects are currently supported by Public Health Service grants and are targeted at elucidating the pathogenesis of major human disease states including diabetes mellitus, renal allograft rejection, asthma, and bronchitis. Each project requires the use of a mass spectrometer for quantitation of trace mediators not readily measurable by other physical, chemical, or immunologic methods or for structural studies of novel biologic products whose identity has not yet been established. Specific projects include: 1.) The participation of eicosanoids and ether lipids in glucose- induced insulin secretion from isolated human pancreatic islets; 2.) The involvement of phosphoinositide hydrolysis products in insulin secretion by islets and the biochemical actions of interleukin 1 on islets; 3.) The role of phosphoinositide-derived messengers including inositol-1,4,5-trisphosphate, diacylglycerols, and inositol-phospho-glycans in insulin action on adipocytes; 4.) The influence of thromboxane and leukotrienes on renal functions during renal allograft rejection and cyclosporin nephrotoxicity; and 5.) Identification of novel eicosanoids from human tracheal epithelial cells and the accumulation of these compounds in response to inflammatory stimuli. These studies require a mass spectrometer with electron impact and negative and positive chemical ionization capabilities. Current access to such an instrument is severely limited, and continued progress on these studies requires the purchase of a mass spectrometer dedicated to use by this group. The members of this group have an extensive publication record of studies applying mass spectrometry to biochemical research problems and can account for full-time utilization of the requested instrument.
