MECHANISMS OF RETINAL DEGENERATION IN USHER SYNDROME TYPE IIA

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 Usher综合征IIa型是最常见的Usher综合征，使其成为世界上耳聋和失明的最重要的遗传原因。我们有明确的证据表明，usherin的短亚型是一种基底膜蛋白，特异性地与视网膜色素上皮细胞上的整合素相互作用。我们还表明，在Ush 2a患者中发现的一些突变破坏了usherin与<$1 <$1整联蛋白相互作用的能力。两种整合素1缺失小鼠和usherin亚型小鼠发生与布鲁赫层基底膜中基质积累相关的视网膜变性，布鲁赫层基底膜是RPE细胞上的<$1 <$1整联蛋白与基底膜usherin的结合界面。总的来说，这些数据表明，usherin与RPE细胞上的± 1 ± 1整联蛋白的结合对于RPE的正常功能至关重要，因此是与Usher综合征IIa型相关的视网膜病理学的主要潜在原因。本研究的具体目的是检验Usher综合征IIa型视网膜变性的中心机制是缺乏Usherin介导的视网膜色素上皮细胞上的<$1 <$1整联蛋白的激活这一假设。由此产生的功能失调的细胞信号直接影响基底膜代谢和感光细胞的健康，最终导致突触畸形和感光细胞凋亡。在我们最初的研究中，我们已经表明usherin亚型小鼠和1整合素缺失小鼠具有非常相似的进行性视网膜变性过程。在这两种动物模型中，视杆细胞光感受器显示出响应于光/暗适应的转导素和抑制素的延迟易位。 在这两种情况下，易位异常之前，感光细胞变性的证据，但同时与ERG检测到的功能异常。 在其他两种Usher综合征动物模型：艾姆斯Waltzer小鼠和Shaker小鼠中也检测到类似的杆状蛋白易位缺陷。此外，已经证明，增加的光暴露在突变体视网膜中产生更快的光感受器变性。

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.