Molecular Studies of Retinal Degeneration in Drosophila

我们的长期目标是揭开遗传性人类致盲疾病的分子遗传学，例如 视网膜色素变性(RP)和老年性黄斑变性(AMD)。基因缺陷会导致 AMD和RP的光感受器细胞死亡是高度不同的，现在包括了超过132个 基因。AMD和RP复杂多样的临床和遗传学表现表明，有多种 疾病的亚型，每一种都有不同的遗传和生化基础。这种复杂性，罕见的 RP和AMD患者眼组织的可用性以及果蝇的广泛知识基础 遗传学，所有这些结合在一起，使果蝇成为研究遗传视网膜的强大动物模型 退化性疾病。我们建议使用果蝇作为一个模型来识别和表征新的基因座 人类致盲疾病，为视网膜退化的分子基础提供了机械性的见解。我们 将使用遗传、生化、细胞生物学、电生理和分子的综合策略 揭示协调蛋白质生物合成的多种分子信号机制的方法 感光细胞。我们的研究重点是那些确保正确折叠、修改、 新合成蛋白质的寡聚组装、质量控制、运输和靶向。这些产品中的缺陷 过程通常会刺激广泛的细胞反应，导致发病，在严重的情况下， 神经退行性变。在这里，我们将描述分子伴侣Calnexin，以及4个新的 Calnexin途径中的功能：cip1、cip2、cip3和cip4。Calnexin是一种分子伴侣，促进 内质网(ER)中新生糖蛋白的正确折叠。离开内质网后，新的 折叠的蛋白质必须被运送到高尔基体，在那里它们经历一系列新的修饰。运输 两个隔室之间的蛋白质通过囊泡的萌发和融合发生。我们将描述 高尔基体囊泡灌流活动所需的一种新的光感受器SNARE蛋白。我们已经证明了 Calnexin、cip1-4和SNARE基因突变导致视紫红质表达缺陷并导致视网膜 退化。我们的发现将被用于筛选人类AMD和RP家系中类似的突变。我们 目的揭示致盲疾病中的新基因，为视网膜分子机制的研究提供新的思路 并为RP和AMD的治疗提供了新的方法。

Our long-term objective is to unravel the molecular genetics of hereditary human blinding diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Genetic defects that lead to photoreceptor cell death in AMD and RP are highly heterogeneous and now include a list of more than 132 genes. The complex and various clinical and genetic findings in AMD and RP suggest that there are multiple subtypes of the diseases, each with a distinct genetic and biochemical basis. This complexity, the infrequent availability of ocular tissues from RP and AMD patients, and the broad base of knowledge of Drosophila genetics, all combine to make Drosophila a powerful animal model for studying inherited retinal degeneration disorders. We propose to use Drosophila as a model to identify and characterize novel loci in human blinding diseases, providing mechanistic insights into the molecular basis of retinal degeneration. We will use an integrated strategy of genetic, biochemical, cell biological, electrophysiological, and molecular approaches to uncover the diverse molecular signaling mechanisms that coordinate protein biosynthesis in photoreceptor cells. Our research focuses on those events that ensure correct folding, modification, oligomeric assembly, quality control, trafficking and targeting of newly synthesized proteins. Defects in these processes often stimulate extensive cellular responses that lead to pathogenesis and,in severe cases, neurodegeneration. Here, we will characterize the molecular chaperone calnexin, and 4 novel loci that function in the calnexin pathway: cipl, cip2, cip3 and cip4. Calnexin is a molecular chaperone thatpromotes the proper folding of nascent glycoproteins in the endoplasmic reticulum (ER).Upon exiting the ER, newly folded proteins must be transported to the Golgi where they undergo a new set of modifications. Transport of proteins between the two compartments occurs via the budding and fusion of vesicles. We will characterize a novel photoreceptor SNARE protein required for vesicularfusion events in the Golgi. We have shown that mutations in calnexin, cip1-4 and the snare gene cause defects in rhodopsin expression and lead to retinal degeneration. Our findings will be used to screen human AMD and RP pedigrees for similar mutations. We aim to uncover novel loci in blinding diseases, provide insights into the molecular mechanisms of retinal degeneration, and offer therapeutic approaches for treating RP and AMD.