The ROS ABC protein (ABCR) plays an important role in retinal rod cells. Genetic studies have linked mutations in the ABCR gene to a number of inherited human diseases including Stargardt's macular degeneration and age related macular degeneration (ARMD). Like other members of the ABC gene family, the ABCR protein is characterized by two nucleotide binding motifs and two transmembrane domains, each consisting of six membrane-spanning helices. Biochemical studies have suggested that this protein may function as a flipase, moving compounds from the lumenal to the cytosolic face of the disc membrane. Pivotal to this function are the ATP binding and hydrolysis, which presumably provide the energy for this translocation process. Nearly all the ABCR mutations identified in patients with recessive Stargardt's, age related macular degeneration, and fundus flavimaculatus map within the ATP binding cassettes. In addition, these domains are highly conserved between species. The overall aim of this application is to carry out a detailed molecular analysis of the ATP binding domains in the energy transduction process. In particular, we wish to test the hypothesis that mutations previously associated with Stargardt's disease and ARMD influence the energy transduction in retinal transport, particularly the ATP binding and hydrolysis step. We shall investigate this question by analyzing the energetics of recombinant proteins harboring mutations in these domains. Information gained from these studies will not only lead to an understanding of the mechanism of action of the ABCR protein, but will also give insight into the molecular basis of the diseases arising from mutations in this gene. This is in keeping with our long-term goal, which is a systematic molecular analysis of genetic mutations that are responsible for inherited visual disorders so that new and accurate therapies can be developed in the near future.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15EY013113-01
Application #
6164726
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
2000-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$158,292
Indirect Cost
Name
Thomas Jefferson University
Department
Biostatistics & Other Math Sci
Type
Schools of Allied Health Profes
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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