The severe loss of photoreceptor cells in retinal degenerative diseases often leads to total blindness. At present, there is no available treatment or cure to the blind. Prospective strategies currently being considered for restoration of vision following rod and cone degeneration include transplantation of normal photoreceptor or progenitor cells and direct electrical stimulation of the surviving retinal neurons via retinal implants. We are exploring another strategy to restore light sensitivity to the degenerate retinas: the expression of light-sensitive membrane channels in surviving second- or third-order retinal neurons. This approach is plausible. First, directly light-gated microbial-type rhodopsins, channelrhodopsins, have been recently cloned. Our preliminary results have shown the ability of functional expression of channerhodopsin-2 (ChR2) in retinal neurons in normal and retinal dystrophic animals in vivo and the capability to depolarize the membrane potential of ChR2-expressing retinal neurons by light. Second, studies in blind patients and in animal models suggest that the second- and third-order retinal neurons remain, in part, preserved in the diseased retinas. Furthermore, it is possible that foreign genes can be introduced into retinal neurons by viral-based gene therapy. A potential advantage of this approach is that it does not involve the introduction of tissues or devices into the retina and, thus, may avoid the immune reactions and biocompatibility complications. The objective of this proposal is to address questions that are fundamental to the feasibility and success of this strategy by using rodent models.
The specific aims of this proposal are: 1) To examine the longevity and biocompatibility of the expression of ChR2 in retinal neurons in vivo and explore the targeting expression of ChR2 in certain functional sub-populations of inner retinal neurons; 2) To characterize the light-evoked current and voltage responses of ChR2 expressing inner retinal neurons; 3) To examine the physiological properties of the surviving inner retinal neurons after photoreceptor degeneration; 4) To characterize the light response properties in the degenerate retinas following the expression of ChR2. These proposed studies could establish the necessary foundation for further work leading to a potential treatment for blinding disorders as well as power techniques with applicability in retinal research. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017130-02
Application #
7270389
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
2006-09-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$365,339
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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