This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Usher syndrome type IIa is the most common of the Usher syndromes, making it the single most important genetic cause of combined deafness and blindness in the world. We have definitive evidence that the short isoform of usherin is a basement membrane protein that specifically interacts with 1 1 integrin on retinal pigment epithelial cells. We also show that some mutations found in humans with Ush2a destroy the ability of usherin to interact with 1 1 integrin. Both integrin 1 null mice and usherin hypomorph mice develop retinal degeneration associated with matrix accumulation in the basement membrane of Bruchs layer, which is the binding interface of 1 1 integrin on RPE cells with basement membrane usherin. Collectively these data suggest that binding of usherin to 1 1 integrin on RPE cells is essential for the RPE to function properly, and thus a principal underlying cause for retinal pathology associated with Usher syndrome type IIa.
The specific aim of this research is to test the hypothesis that a central mechanism for retinal degeneration in Usher syndrome type IIa is the absence of usherin-mediated activation of 1 1 integrin on retinal pigment epithelial cells. The resulting dysfunctional cell signaling directly affects basement membrane metabolism and photoreceptor cell health, culminating in synaptic malformations and photoreceptor apoptosis. In our initial studies, we have shown that both the usherin hypomorph mouse and 1 integrin null mouse have a very similar course of progressive retinal degeneration. In both animal models, rod photoreceptors show delayed translocation of transducin and arrestin in response to light/dark adaptation. In both cases, the translocation abnormalities were noted prior to evidence of photoreceptor degeneration, but concurrent with functional abnormalities detectable by ERG. Similar defects of rod protein translocation were also detected in two other Usher Syndrome animal models: Ames Waltzer mouse and Shaker mouse. Furthermore, it was demonstrated that increased light exposure produces more rapid photoreceptor degeneration in the mutant retinas.
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