MECHANISMS OF RETINAL DEGENERATION IN USHER SYNDROME TYPE IIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Usher综合征IIa型是最常见的Usher综合征，使其成为世界上导致耳聋和失明的单一最重要的遗传原因。我们有确凿的证据表明，usherin的短亚型是一种基底膜蛋白，它与视网膜色素上皮细胞上的1整合素特异性地相互作用。我们还表明，在携带Ush2a的人类中发现的一些突变破坏了Ush2a与整合素1相互作用的能力。整合素1缺失小鼠和引导素低畸形小鼠均表现为视网膜变性，伴随着Bruchs层基底膜的基质堆积，基底膜是1整合素与RPE细胞的结合界面。总而言之，这些数据表明，RPE细胞上的usherin与整合素的结合对于RPE的正常运行是必不可少的，因此是与Usher综合征IIa相关的视网膜病理的主要潜在原因。这项研究的具体目的是验证一种假说，即Usher综合征IIa型视网膜变性的一个中心机制是缺乏由总管蛋白介导的视网膜色素上皮细胞整合素的激活。细胞信号转导功能障碍直接影响基底膜代谢和光感受器细胞健康，最终导致突触畸形和光感受器细胞凋亡。在我们的初步研究中，我们已经表明，引导素低畸形小鼠和整合素缺失小鼠都有非常相似的进行性视网膜退化过程。在这两种动物模型中，视杆感受器对光/暗适应的反应表现出转导蛋白和arrestin的延迟移位。在这两种情况下，易位异常在光感受器退化的证据之前就被注意到了，但同时伴随着ERG可检测到的功能异常。在另外两个亚瑟综合征动物模型中也发现了类似的杆状蛋白易位缺陷：Ames Waltzer小鼠和Shaker小鼠。此外，研究还表明，增加光照会导致突变型视网膜中光感受器更快的退化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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 Bruch's 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.