Dissecting the molecular function of basigin a protein required for normal struct

描述（由申请人提供）：眼睛的退行性疾病，特别是外视网膜营养不良，是无法治愈的失明的主要原因。一种可能在视网膜病变中起作用的基因是基底蛋白基因（也就是人类的EMMPRIN）。Basigin是一个基因家族的成员，该基因家族编码参与细胞相互作用的细胞表面IgG蛋白。我们正以果蝇为模型系统，研究盆地蛋白在基本视觉系统细胞生物学和视觉系统功能中的作用。我们已经在果蝇的视觉系统中发现了几种盆地功能，其中许多功能与脊椎动物中描述的功能一致。例如，盆状蛋白突变小鼠和眼睛中盆状蛋白功能突变的马赛克蝇（Clamp et al., 2003; Curtin et al., 2007）表现出异常的视网膜电图（ERGs）。Basigin突变小鼠显示光感受器（PC）细胞结构改变（Ochreitor et al., 2001）。果蝇basigin是正常感光细胞结构所必需的（Curtin et al., 2005）。Basigin与鸟类视觉系统分离细胞中的神经元-神经胶质相互作用有关（Fadool和Linser， 1993）。果蝇基底蛋白是视神经层中神经元-胶质细胞相互作用的必要条件（Curtin et al., 2007）。所有这些巧合都有力地证明，我们对果蝇视网膜中基底蛋白分子功能的了解将有助于我们了解它在哺乳动物视网膜中的功能。最后，苍蝇和老鼠的盆蛋白都能修复马赛克盆蛋白果蝇视觉系统的缺陷，这表明哺乳动物的盆蛋白可以与果蝇的盆蛋白进行类似的分子接触（Curtin et al., 2005,2007）。我们的主要目标是了解基底素促进正常视觉系统结构和功能的分子机制。我们的初步数据表明，盆地蛋白形成蛋白质复合物。我们使用酵母双杂交实验来检测膜上的蛋白质相互作用，以鉴定推定的盆地相互作用蛋白和编码它们的基因。我们将使用遗传/功能研究和生物化学来确定这些蛋白质相互作用的功能意义，以及探索特定的盆状蛋白修饰对盆状蛋白细胞功能的意义。这种能够独立于动物的其他部分来操纵眼睛的基因组成的能力为我们提供了一个特殊的系统来研究盆状蛋白的分子功能和盆状蛋白相互作用的基因。

DESCRIPTION (provided by applicant): Degenerative diseases of the eye, specifically outer retinal dystrophies, are a major cause of incurable blindness. One gene that may play a role in retinopathy is the basigin gene (aka EMMPRIN in humans). Basigin is a member of a gene family that encodes cell surface IgG proteins that are implicated in cellular interactions. We are using Drosophila as a model system to study basigin's role in basic visual system cell biology and visual system function. We have identified several basigin functions in the visual system using flies, many of which are co-incident with functions described in vertebrates. For example, basigin mutant mice show abnormal electroretinograms (ERGs) as do mosaic flies in which basigin function is mutant in the eye (Clamp et al., 2003; Curtin et al., 2007). Basigin mutant mice show altered photoreceptor (PC) cell structure (Ochreitor et al., 2001). Drosophila basigin is required for normal photoreceptor cell structure (Curtin et al., 2005). Basigin has been implicated in neuron-glia interaction in dissociated cells from the avian visual system (Fadool and Linser, 1993). Drosophila basigin is necessary for neuron-glia interactions in the optic lamina (Curtin et al., 2007). All these co-incidences argue strongly that what we learn about basigin molecular function in the Drosophila retina will help us understand its function in the mammalian retina. Lastly, both fly and mouse basigin can rescue the defects seen in the visual system of mosaic basigin flies showing that mammalian basigin can make similar molecular contacts as Drosophila basigin (Curtin et al., 2005, 2007). Our main goal is to understand the molecular mechanisms by which basigin acts to promote normal visual system structure and function. Our preliminary data show that basigin forms protein complexes. We are using a yeast two-hybrid assay designed to detect protein interactions at the membrane to identify putative basigin-interacting proteins and the genes that encode them. We will use genetic/ functional studies and biochemistry to identify the functional significance of these protein interactions as well as exploring the significance of specific basigin protein modifications for basigin cellular functions. The ability to specifically manipulate the genetic make-up of the eye independent of the rest of the animal provides us with an exceptional system to study the molecular function of basigin and the genes for basigin interacting proteins. PUBLIC HEALTH RELEVANCE: The proposed studies have relevance to human health by exploring the molecular role of basigin/EMMPRIN in the maintenance and function of the visual system. The project's main aim is to identify basigin-interacting proteins in the eye and to analyze the genes that code for these proteins so that we can better understand how basigin affects visual system development and function.