Grant: $368,750 - National Institutes of Health - Jun. 3, 2009
29% voted satisfied - 71% voted not satisfied - 7 vote(s) cast
Award Description: The broad objective of this project is to prevent degeneration of cone photoreceptors, which are essential for human color vision. In a disease such as Leber Congenital Amaurosis (LCA), the levels of the native chromophore of visual pigments, the Vitamin A derivative 11-cis retinal, is absent or highly reduced. In mouse models for LCA, cone visual pigment proteins (opsins) are highly mislocalized and cone cells subsequently die. Damage seems to be most severe with blue cones. This pattern parallels the pathogensis of LCA. Treating these mice with 11-cis retinal at an early age in the dark preserves healthier cones, suggesting that opsin?s binding of 11-cis retinal is an important step in preventing cone death. A drawback to 11-cis retinal itself as a therapeutic agent is that it is destroyed once it combines with the opsin and exposed to light. The working hypothesis for this proposal is that in the absence of the native chromophore, chemical compounds that can mimic the effects that 11-cis retinal has on the cone opsins will also mimic the cellular effects on the cone photoreceptors. The main advantage of such compounds is that the treatment period will not require constant dark conditions. At the molecular level, cone opsins are constitutively active, and 11-cis retinal deactivates the opsins. A library of compounds that are analogs of 11-cis retinal will be tested for their effectiveness in turning off human cone opsins as judged by their abilities to activate transducin. Compounds that effectively deactivate the opsins will then be tested in isolated cone photoreceptor cells to ensure they are not toxic to cells and they are able to deactivate cone opsins inside a living cell. Compounds found to meet these criteria will be tested in 2 mouse models of LCA to determine if they can prevent the rapid degeneration of cone photoreceptor cells as judged by fluorescence microscopy and electroretinography. The ability to preserve the viability of cone photoreceptor cells in those afflicted with LCA will be a critical step to restoring visual acuity.
Project Description: As defined in the Award Description field.
Jobs Summary: Postdoc Scholar (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jun. 3, 2009. Help expand these official descriptions using the wiki below.