Molecular Studies of Retinal Degeneration in Drosophila

描述（由申请人提供）：拟议研究的目标是 利用果蝇作为研究人类遗传性疾病的模型 导致视网膜变性并最终失明[色素性视网膜炎 (RP) 和年龄相关性黄斑变性（AMD）]。的复杂性和变化 人类 RP 和 AMD 表明该疾病有多种亚型，每种亚型 具有独特的遗传和生化基础。这种复杂性、罕见性 RP 和 AMD 患者眼组织的可用性，以及广泛的基础 果蝇分子遗传学知识相结合，使果蝇成为 用于研究遗传性视网膜变性疾病的强大动物模型。我们 建议采用生化、细胞生物学、 电生理学、遗传和分子方法来识别和 描述导致蛋白质运输和靶向缺陷的突变。 我们已经鉴定出三种显示分泌途径的果蝇突变系 缺陷和视网膜病理学。我们将识别相应的基因并 对它们进行详细的遗传和分子分析。此外，我们将 继续筛选 12,000 个单独的突变株系以检测视网膜变性。的 筛选基于简单的形态学表型，可以在 解剖显微镜下的活苍蝇。定义成分的突变体 分泌途径和蛋白质靶向将受到详细的 表征。我们的发现将用于筛选高度定义的集合 人类 AMD 和 RP 患者的类似缺陷。遗传分析在 果蝇仍然是快速识别基因的有力手段 对于蛋白质运输和正常光感受器功能至关重要。它是 预计本研究中确定的基因将为 人类 AMD 和 RP 的遗传学。

DESCRIPTION (provided by applicant): The objective of the proposed research is to utilize Drosophila as a model for studying hereditary human diseases that cause retinal degeneration and eventual blindness [retinitis pigmentosa (RP) and age-related macular degeneration (AMD)]. The complexity and variations of human RP and AMD suggest that there are multiple subtypes of the diseases, each with distinct genetic and biochemical bases. This complexity, the infrequent availability of ocular tissues from RP and AMD patients, and the broad base of knowledge of Drosophila molecular genetics, combine to make Drosophila a powerful animal model for studying inherited retinal degeneration disorders. We propose to use an integrated strategy of biochemical, cell biological, electrophysiological, genetic, and molecular approaches to identify and characterize mutations that cause defects in protein transport and targeting. We have identified three mutant lines of flies that display secretory pathway defects and retinal pathology. We will identify the corresponding genes and subject them to a detailed genetic and molecular analysis. In addition, we will continue to screen 12,000 individual mutant lines for retinal degeneration. The screen is based on a simple morphological phenotype that may be screened in live flies under the dissecting microscope. Mutants that define constituents of the secretory pathway and protein targeting will be subjected to a detailed characterization. Our findings will be utilized to screen a highly defined set of human AMD and RP patients for similar defects. Genetic analysis in Drosophila remains a powerful means of rapidly identifying genes that are essential for protein trafficking and normal photoreceptor function. It is anticipated that genes identified in this study will provide insights for the genetics of AMD and RP in humans.