Specific Aims Broadly, there are two major specific aims for the coming project period. One is the identification of the excitatory molecule for the TRP/TRPL channels and the other is the detailed analysis of three mutants that remain uncharacterized. a. Search for the excitatory molecule for TRP/TRPL channels. This project is a direct continuation of the inaE project completed in the previous project period and represents an attempt to finally close the chapter on the long-standing search for arguably the most sought-after molecule in the field. There will be two basic strategies: i) to identify the excitatory molecule by exogenous application of candidate molecules in whole-cell recordings, and ii) to attempt to obtain genetic evidence as to whether or not monoacylglycerol lipase (MAGL) is involved in the channel activation process by identifying the MAGL gene involved and isolating mutations in the gene. The third part of this aim is to explore whether or not diacylglycerol (DAG) has a synergistic enhancing role in channel excitation even though it has no direct excitatory role itself. b. Analysis of three mutants selected from those that remain uncharacterized. Two of these, P226 and ninaF, were chosen in part because we have made striking progress in the preliminary identification of the genes harboring the lesions responsible for the phenotypes. The third mutant, US2985, was chosen solely on the basis of its interesting phenotype. In the case of P226, we will explore the preliminary hypothesis that its dark adaptation-dependent PDA phenotype is related to metarhodopsin deactivation by extensive, multiple phosphorylation. Because the P226 gene has been tentatively identified to be an ortholog of Usher syndrome genes, the project may shed light on the mechanism of retinal degeneration in Usher syndrome. In the ninaF project, we will explore the hypothesis that the protein encoded by this gene performs a function related to those of NINAC myosin III. In the US2985 project, we will explore the hypothesis that this mutant is impaired in Ca2+-mediated adaptation, but not in Ca2+-mediated activation of response. The project has the potential for identifying a protein specifically involved in Ca2+-mediated adaptation.
Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. Discovery of an important link between human AMD and blindness in mice may reveal an underlying cause of AMD and lead to therapies for reducing the severity of AMD.
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