Lysosomal Proteases and Retinal Degeneration

溶酶体蛋白酶和视网膜变性

• 批准号: 6959788
• 负责人: PATRICK J. DOLPH
• 金额: $ 15.99万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6959788
• 关键词: Drosophilidae; apoptosis; aspartic endopeptidases; cysteine endopeptidases; endocytosis; enzyme activity; green fluorescent proteins; guinea pigs; immunocytochemistry; lysosomes; polymerase chain reaction; retina degeneration; visual photoreceptor

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.

描述（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。像许多神经元变性疾病一样，视网膜变性的最终结果是被称为细胞凋亡的细胞死亡途径的激活。在人类和其他模型系统中，已经确定了许多导致视网膜变性的突变。然而，这些分子缺陷最终如何参与凋亡机制在几乎所有情况下都是未知的。我们的实验室使用果蝇作为模型系统来研究视网膜变性。特别是，我们专注于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，在那里它聚集并最终触发感光细胞凋亡。最近，我们已经证明，一类蛋白酶称为组织蛋白酶是在这一退行性过程中的工具，暗示它们作为感光细胞和凋亡细胞死亡的特定突变之间的可能联系。在这项资助中，我们计划通过以下方式研究组织蛋白酶在视网膜变性中的作用：1）检测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）检测组织蛋白酶中特定突变对视网膜变性的影响，3）检测关键组织蛋白酶底物在视网膜变性过程中是否被切割。组织蛋白酶从未涉及视网膜变性，因此这项工作将提供一个新的感光细胞变性的分子机制。此外，由于有许多可用的组织蛋白酶抑制剂，因此这项工作有可能为视网膜疾病提供潜在的治疗方法。