Molecular Studies of Retinal Degeneration in Drosophila

我们的长期目标是解开遗传性人类致盲疾病的分子遗传学，例如 色素性视网膜炎（RP）和年龄相关性黄斑变性（AMD）。基因缺陷导致 AMD和RP中的感光细胞死亡是高度异质性的，现在包括超过132个 基因. AMD和RP中复杂多样的临床和遗传发现表明， 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， RP和AMD患者眼组织的可用性，以及果蝇的广泛知识基础 所有这些联合收割机使果蝇成为研究遗传性视网膜病变的有力动物模型 变性疾病我们建议使用果蝇作为模型，以确定和表征新的基因座， 人类致盲性疾病，提供视网膜变性的分子基础的机制见解。我们 将采用遗传、生物化学、细胞生物学、电生理学和分子生物学的综合策略， 方法来揭示不同的分子信号机制，协调蛋白质的生物合成， 感光细胞我们的研究重点是那些确保正确折叠，修改， 寡聚体组装、质量控制、运输和靶向新合成的蛋白质。这些缺陷 这些过程经常刺激导致发病的广泛的细胞反应，在严重的情况下， 神经变性在这里，我们将描述分子伴侣钙连接蛋白和4个新的基因座， 在钙连接蛋白途径中起作用：Cip 1、Cip 2、Cip 3和Cip 4。钙连接蛋白是一种分子伴侣， 新生糖蛋白在内质网（ER）中的正确折叠。 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出芽和融合发生。我们将描述 一种新的感光陷阱蛋白所需的囊泡融合事件在高尔基体。我们已经证明 钙连接蛋白、cip 1 -4和snare基因的突变引起视紫红质表达的缺陷， 退化我们的研究结果将用于筛选人类AMD和RP家系的类似突变。我们 旨在揭示致盲疾病的新位点，为视网膜病变的分子机制提供见解， 为RP和AMD的治疗提供了新的思路。

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.