EXCEED THE SPACE PROVIDED. The ultimate goal of the research is to understand the mechanisms responsible for diseases that affect photoreceptors to cause blindness. This information is necessary for the development-of rational therapies to treat photoreceptor dysfunction. An essential step toward the realization of this goal is to have a detailed understanding of how photoreceptors work. For this reason, the proposed studies are designed to investigate the molecular mechanisms that are responsible for the recovery and light adaptation of photoresponses in vertebrate retinal rods. This will be done by using functionally intact rods to establish the basis of normal rod physiology and to assay the affects of selective changes in the underlying molecular machinery. Light responses will be recorded in whole-cell voltage clamp from isolated lizard rod outer segments and internal dialysis will used to introduce probes to either monitor light-evoked changes in intracellular signals or to alter specific steps in the phototransduction cascade. These experiments will be combine with optical techniques to locally excite the transduction cascade by two-photon activation of rhodopsin and to measure internal Ca using fluorescent indicators. The dialyzed rod outer segment preparation will be used to test the functional and quantitative predictions of molecular mechanisms that have been proposed on the basis of biochemical studies on cell free systems. The research will focus on documenting the molecular events in inactivation of the transduction cascade and their Ca dependence. The same techniques will be used to investigate the changes in the transduction cascade that occur during background adaptation and to establish the properties of the intracellular signal(s) that is responsible for adaptation. PERFORMANCE SITE ========================================Section End===========================================
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