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.

Public Health Relevance

Retinal blood vessel permeability contributes to loss of vision in many of the leading causes of blindness in the United States. These studies will develop a specific therapeutic to a target molecule that appears central to the regulation of blood vessel permeability. These studies are relevant to public health by providing compounds that prevent retinal blood vessel leakiness and edema in animal models that will be available for clinical evaluation to preserve sight in diabetes, uveitis and macular degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY023725-01A1
Application #
8727240
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (91))
Program Officer
Shen, Grace L
Project Start
2014-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$499,870
Indirect Cost
$159,631
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109