Molecular Studies of Retinal Degeneration in Drosophila

描述(由申请人提供)：建议研究的目标是 利用果蝇作为研究遗传性人类疾病的模型 导致视网膜变性和最终失明[视网膜色素变性(RP) 和老年黄斑变性(AMD)]。的复杂性和变化性 人类RP和AMD表明存在多种亚型的疾病，每种亚型 具有独特的遗传和生化基础。这种复杂性，罕见的 RP和AMD患者眼组织的可获得性，以及 果蝇分子遗传学的知识，结合在一起使果蝇成为 研究遗传性视网膜变性疾病的强大动物模型。我们 建议使用生化、细胞生物学、 电生理学、遗传学和分子生物学方法来鉴定和 确定导致蛋白质运输和靶向缺陷的突变的特征。 我们已经鉴定出三个显示分泌途径的果蝇突变系 缺陷和视网膜病理。我们将确定相应的基因和 让他们接受详细的遗传和分子分析。此外，我们还将 继续筛选12,000个突变株系的视网膜变性。这个 筛选基于一个简单的形态表型，该表型可以在 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 人物刻画。我们的发现将被用来筛选一组高度定义的 人类AMD和RP患者的相似缺陷。中国的遗传分析 果蝇仍然是一种快速识别基因的有效手段 对于蛋白质运输和正常的光感受器功能是必不可少的。它是 预计这项研究中发现的基因将为 人类AMD和RP的遗传学研究。

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.