Molecular Studies of Retinal Degeneration in Drosophila

描述（由申请人提供）：拟议研究的目的是 利用果蝇作为研究人类遗传性疾病的模型， 导致视网膜变性和最终失明[视网膜色素变性（RP） 和年龄相关性黄斑变性（AMD）]。的复杂性和多样性， 人RP和AMD表明存在多种亚型的疾病， 具有独特的遗传和生化基础。这种复杂性， RP和AMD患者眼组织的可用性，以及 果蝇分子遗传学知识，联合收割机使果蝇成为 研究遗传性视网膜变性疾病的强大动物模型。我们 建议使用生物化学，细胞生物学， 电生理学、遗传学和分子方法来识别和 表征导致蛋白质转运和靶向缺陷的突变。 我们已经确定了三个突变系的苍蝇，显示分泌途径 缺陷和视网膜病理学。我们将识别相应的基因， 对它们进行详细的基因和分子分析。此外，我们将 继续筛选12,000个视网膜变性的突变株。的 筛选是基于一个简单的形态表型，可以筛选在 活苍蝇在解剖显微镜下。突变体定义了 分泌途径和蛋白质靶向将受到详细的 特征化我们的研究结果将被用来筛选一个高度定义的集 人类AMD和RP患者的相似缺陷。遗传分析 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感光功能至关重要。是 预计这项研究中发现的基因将为人类的遗传学研究提供新的见解。 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.