Lysosomal Proteases and Retinal Degeneration

溶酶体蛋白酶和视网膜变性

• 批准号: 7105523
• 负责人: PATRICK J. DOLPH
• 金额: $ 15.61万
• 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/7105523
• 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（由申请人提供）：遗传和零星的视网膜变性导致每年成千上万的人的视力丧失。像许多神经元变性疾病一样，视网膜变性的最终结果是称为凋亡的细胞死亡途径的激活。在人类和其他模型系统中，已经确定了许多引起视网膜变性的突变。但是，这些分子缺陷最终如何使凋亡机制在几乎所有情况下都尚不清楚。我们的实验室使用果蝇果蝇Melanogaster作为模型系统来研究视网膜变性。特别是，我们专注于一种视网膜变性，其中光受体视紫红质从质膜内部内部化为细胞质，在那里它聚集并最终触发感光细胞细胞细胞凋亡。最近，我们证明了一类称为组织蛋白酶的蛋白酶在这种退化过程中具有重要作用，这将它们视为感光细胞中特定突变与凋亡细胞死亡之间的可能联系。在这笔赠款中，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）测试在视网膜变性过程中，在视网膜变性过程中，calter蛋白在视网膜变性过程中是否表现出细胞内的易位，2）检查到视网膜变性中特异性突变对载蛋白的影响，以及3）测试关键的载细胞蛋白酶底物是否在视网膜变性过程中裂解。组织蛋白酶从未与视网膜变性有关，因此这项工作将为感光细胞变性提供新颖的分子机制。此外，由于有许多组织蛋白酶抑制剂可用，因此这项工作有可能为视网膜疾病提供潜在的疗法。