Lysosomal Proteases and Retinal Degeneration

描述（由申请人提供）：遗传性和散发性视网膜变性每年导致数十万人视力丧失。像许多神经元退行性疾病一样，视网膜变性的最终结果是激活称为细胞凋亡的细胞死亡途径。在人类和其他模型系统中，已经确定了许多引起视网膜变性的突变。然而，在几乎所有的病例中，这些分子缺陷最终如何参与凋亡机制尚不清楚。本实验室以果蝇黑腹果蝇为模型系统研究视网膜变性。我们特别关注一种形式的视网膜变性，其中光受体视紫红质从质膜内化到细胞质，并在细胞质中聚集并最终引发光受体细胞凋亡。最近，我们已经证明了一类被称为组织蛋白酶的蛋白酶在这种退行性过程中起着重要作用，这意味着它们可能是光感受器细胞特定突变和凋亡细胞死亡之间的一种联系。在这项资助中，我们计划通过以下方式来研究组织蛋白酶在视网膜变性中的作用：1)测试组织蛋白酶在视网膜变性过程中是否表现出细胞内易位，2)检查组织蛋白酶的特定突变对视网膜变性的影响，以及3)测试在视网膜变性过程中是否有一个关键的组织蛋白酶底物被切割。组织蛋白酶从未涉及视网膜变性，因此这项工作将为光感受器细胞变性提供新的分子机制。此外，由于有许多组织蛋白酶抑制剂可用，因此这项工作可能为视网膜疾病提供潜在的治疗方法。

DESCRIPTION (provided by applicant): Inherited and sporadic retinal degeneration leads to vision loss in hundreds of thousands of people each year. Like many neuronal degenerative diseases, the end result of retinal degeneration is the activation of a cell death pathway termed apoptosis. In humans, and in other model systems, many mutations have been identified that cause retinal degeneration. However, how these molecular defects eventually engage the apoptotic machinery is unknown in nearly all cases. Our laboratory uses the fruit fly Drosophila melanogaster as a model system to study retinal degeneration. In particular we focus on one form of retinal degeneration where the light receptor rhodopsin is internalized from the plasma membrane to the cytoplasm where it aggregates and eventually triggers photoreceptor cell apoptosis. Recently, we have demonstrated that a class of proteases called cathepsins is instrumental in this degenerative process, implicating them as a possible link between specific mutations in the photoreceptor cell and apoptotic cell death. In this grant we plan to investigate the role of cathepsins in retinal degeneration by: 1) testing whether cathepsins exhibit intracellular translocation during the retinal degeneration process, 2) examining the effect of specific mutations in cathepsins on retinal degeneration, and 3) testing whether a key cathepsin substrate is cleaved during retinal degeneration. Cathepsins have never been implicated in retinal degeneration, and therefore this work will provide a novel molecular mechanism for photoreceptor cell degeneration. Moreover, since there are numerous cathepsin inhibitors available, there is the possibility that this work could provide potential therapies for retinal disease.