The overall aim of this research is to develop more effective treatment for fungal keratitis. To accomplish this objective, there is a need to study the separate but related infectious and inflammatory process that occur simultaneously and to develop pharmacological treatment that combines effective antifungal and antiinflammatory measures. The PI will examine the role of ocular cyclooxygenases in the inflammatory response to fungal infection in the cornea and anterior uvea. The regulation and cellular distribution of rabbit ocular cyclooxygenase 1 and 2, which he have recently cloned, will be established during thevarious stages of fungal keratitis. Also, the integrity of the bolls aqueous barrier, recruitment of inflammatory cells, and changes inthe aqueous prostaglandin levels will be establihsed. These experiments will allow the PI to better understand the molecular basis of fungal keratitis. Changes in the expression of Candida CYP51, which is required for fungal cell wall production and is a target of azole compounds, will be determine and used as a marker of the metabolic state of viable fungi during antifungal treatment. By using this method along with quantitative isolate recovery the PI will be able to determine both the metabolic state of fungi and the number of azole antifungal compounds. Finanly, he will determine the efficacy of azole antifungal agents alone and in combination with antiinflammatory agents using our model of fungal keratitis. This will be accomplished by methods that we have established to assess the ocular inflammatory response and metabolic state of the invading fungi.
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