application) The Research: This project will investigate the regulation of intestinal epithelial chemokine secretion as well as down-regulating this chemokine secretion via lipoxins- endogenously biosynthesized anti-inflammatory eicosanoids. Specifically, this project has three major aims. One, define the role of calcium signaling in regulating epithelial secretion of IL-8 (a potent neutrophil chemoattractant). Two, elucidate the interactions between the apical surface of the intestinal epithelium that activate the signals that mediate epithelial IL-8 secretion. Three, investigate the molecular mechanism by which lipoxin A4 down-regulates epithelial chemokine secretion and whether lipoxin A4 stable analogs can down-regulate intestinal inflammation in a mouse model of colitis. As epithelial chemokine secretion is thought to drive the neutrophil movement that defines active intestinal inflammation, this research will increase our understanding of the molecular basis of active inflammation. Since chronic inflammatory diseases of the intestine may result from aberrant mucosal immune responses to normal gut microflora, this project's focus on bacterial-induced inflammation is particularly germane to the understanding of these debilitating disorders. Further, this work will further develop the very promising therapeutic strategy of treating intestinal inflammation via lipoxin stable analogs. The Candidate: Dr. Gewirtz has a solid background in both signal transduction and bacterial-epithelial-neutrophil interactions. He has been very productive in these areas as evidenced by his publications including 4 first authored original research papers published (or in press) within the last year. Following this additional period of mentored research, Dr. Gewirtz will be well positioned for a fruitful career as an independent NIH-funded investigator. The Mentors: The sponsor Dr. Madara and co-sponsor Dr. Serhan are widely recognized as experts in the fields of bacterial-epithelial-neutrophil interactions and eicosanoid biochemistry respectively. Further, both have an extensive history of successfully training developing investigators. The Environment: Dr. Gewirtz has been given laboratory space in Dr. Madara's lab in the epithelial pathobiology division of Emory University's Pathology department. In addition to containing an extensive array of basic research equipment, this lab space contains a new thermostatted spectrofluorimeter to be used primarily by Dr. Gewirtz.
