The overall long-term goal is to understand cellular mechanisms in photoreceptor and RPE cells, especially those mechanisms related to the turnover of phototransductive proteins.
The specific aims of the present proposal focus on understanding the retinal function of the Usher 1B protein, myosin VIIa, which participates in this turnover process. Usher syndrome 1 (USH1) is a devastating disorder in which children are born with profound deafness and vestibular dysfunction. Later, they develop retinal degeneration. USH1 can be caused by mutations in any one of seven genes, although the most common genetic defect is in myosin VIIa (MYO7A). Our past studies have localized myosin VIIa in the retina, identified retinal phenotypes in myosin VIIa-mutant mice, and demonstrated actin-based motility of native myosin VIIa. The in vivo bias of these studies has permitted the development of physiologically relevant hypotheses about the retinal function of myosin VIIa. The proposed research tests these hypotheses at a more molecular and cellular level. We will investigate the role of myosin VIIa in the clearance of phagosomes from the apical to the basal region of the retinal pigmented epithelium (RPE). We will identify binding proteins in the RPE and photoreceptor cells, focusing on those that might link myosin VIIa to indicated roles in the localization of phagosomes, melanosomes, and opsin. We will test whether rhodopsin regeneration is inhibited in myosin VIIa-null RPE, as suggested by the finding that susceptibility to light damage is decreased in the absence of myosin VIIa. Lastly, we will investigate other USH1 proteins in the retina, and whether they interact with myosin VIIa. These studies will provide new information on the retinal function of myosin VIIa, and help elucidate the basis of retinal disease in USH1B.
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