Retinitis pigmentosa (RP) constitutes a group of genetically-mediated, degenerative retinal diseases that display a broad range of phenotypes. There is appreciable heterogeneity in the pathologies that underlie the various forms of RP, but of the known cases, a substantial percentage arise as a consequence of mutations in rhodopsin or other rod-specific proteins. However, despite the fact that the genetic defect is expressed solely in the rod photoreceptors, otherwise healthy cone photoreceptors invariably die, resulting in severe visual impairment. The principal goal of this proposal is to test the hypothesis that the spread of the disease from dying rods to genetically normal cones is a form of """"""""bystander"""""""" effect, mediated by the gap junctions that exist between these photoreceptor subtypes. On this view, agents that trigger the apoptotic process permeate the intercellular gap-junctional channels to carry proapoptotic signals from diseased rods to neighboring cones. If gap junctions are a significant factor in the non-cell-autonomous spread of photoreceptor degeneration, blocking transmission through these channels may provide a novel form of therapeutic intervention that would enable cones to be spared the fate of their neighbors. The experiments we plan to conduct will help to determine whether the cone photoreceptors of transgenic mice that express rod-specific gene defects exhibit a significantly higher survival when the gap-junctional protein (connexin36) that couples their rods and cones is disrupted. Cx36 """"""""knockout"""""""" mice are available, and we propose to cross them with mice expressing various rod-specific mutations that result in rod-cone dystrophy. Cone structure and function will be assessed by a panel of histological, immunocytochemical, and electrophysiological methods. In addition, we plan to conduct a series of molecular biological and biochemical studies to examine further connexin expression in mammalian photoreceptors, and to identify proapoptotic agents that are able to permeate the intercellular channels.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
5R03EY014557-03
Application #
7012179
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Mariani, Andrew P
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$152,207
Indirect Cost
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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