Rod and cone outer segments are unique compartments of photoreceptor cells where the process of phototransduction occurs. The overall goal of this research program is to identify and characterize outer segment membrane proteins and elucidate their role in i) the visual process, ii) outer segment morphogenesis, structure, and renewal, and iii) inherited retinal degenerative diseases.
The specific aims of the current grant period are as follows: 1) To study the structural, functional, and regulatory properties of ABCR, the photoreceptor ATP binding cassette (ABC) transporter of photoreceptors, and determine its cellular and subcellular distribution in rod and cone photoreceptors. 2) To develop a heterologous cell (COS-1) system to express wild-type and mutant forms of ABCR for structure-function analyses. This system will be used to determine how missense mutations in ABCR implicated in Stargardt disease alter the structure of ABCR and its possible function as a transporter. 3) To identify, clone, characterize and localize novel low abundant rod outer segment membrane proteins as a first step in determining their role in outer segment structure, function and renewal and their possible involvement in inherited retinal degenerative diseases. For these studies, a variety of current biochemical, molecular biology, cell biology and biophysical methods will be employed along with a unique panel of highly specific monoclonal antibodies and cDNAs to ABCR and novel, undefined outer segment proteins. The results of these studies should lead to new information about the morphogenesis, structure and function of rod and cone outer segments and provide insight into the role of ABCR in the visual cycle and retinal degenerative diseases including Stargardt macular dystrophy and age-related macular degeneration.
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