Discovering novel atypical PKC inhibitors as in vivo chemical probes - Supplement to Promote Diversity

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DESCRIPTION (provided by applicant): Macular Edema contributes to many of the leading causes of blindness in America including diabetes, age related macular degeneration and uveitis. Currently, a wide number of studies reveal that altered expression of cytokines, including vascular endothelial growth factor and tumor necrosis factor act to increase blood vessel permeability. Further, research from our laboratory, as well as others, reveals activation of atypical protein kinase C isoforms are required for the permeability response for these and other permeabilizing factors. By screening a commercially available library, we have already identified a class of inhibitors for this target and in this grant we propose to combine medicinal chemists, structural biologists and cellular and molecular physiologists to develop compounds that control retinal blood vessel permeability in multiple models of eye disease. Importantly, measures of retinal function will mimic clinical assessments. The successful completion of these studies will provide a robust chemical pharmacophore, pharmacokinetic analysis, mechanism of action and in vivo effectiveness for atypical protein kinase C inhibitors to treat macular edema with specific leads available for clinical trials.