PATHOGENESIS OF OCULAR ALBINISM

黑色素保护眼睛免受太阳辐射的损害。 遗传性疾病，如白化病，减少眼睛色素沉着， 与显著的发病率相关。 拟议研究的目标 是在分子水平上理解特定基因的功能 黑色素的合成和包装所涉及的产品， 影响眼睛色素沉着的遗传性疾病的发病机制， 皮肤，导致眼皮肤白化病。 眼睛是一个理想的系统， 由于高浓度的 眼组织中的黑色素细胞以及眼色素沉着发生的事实 在一个可预测的产后时间过程中。 拟议的工作将需要 优势的眼睛和毛色的遗传学研究在近交系 鼠标解决三个具体目标： 1.表征红点稀释位点的产物， 其结构、合成和亚细胞分布。的假设 这种蛋白质用于将黑色素体膜与黑色素连接， 测试黑素体基质。 2.为了验证这一假设，即编码蛋白质之间的相互作用， 白化病、褐色、板色和红褐色稀释基因座在 调节眼部色素沉着。 将确定这些相互作用， 它们对这些细胞的功能和亚细胞运输的影响 蛋白质将被定义。 亚细胞分级分离，抗肽 抗血清、生化分离技术、酶功能测定和 将利用黑色素的化学分析来检验这一假设。 3.了解特定突变的发病机制（遗传性疾病） 其影响这些蛋白质并因此减少眼部色素沉着。的 在这些基因座上确定的突变对表达、功能和 它们各自的基因产物的亚细胞分布和 眼黑素细胞中的其他三种感兴趣的蛋白质取自 将分析从出生到成年的近交系小鼠。

Melanin protects the eye from the damaging effects of solar radiation. Genetic diseases such as albinism, which diminish ocular pigmentation, are associated with significant morbidity. The goals of the proposed research are to understand, at the molecular level, the functions of specific gene products involved in the synthesis and packaging of melanin, and the pathogenesis of genetic disorders which affect pigmentation in the eye and skin, resulting in oculocutaneous albinism. The eye is an ideal system in which to address these problems because of the high concentration of melanocytes in ocular tissue and the fact that ocular pigmentation occurs over a predictable postnatal time course. The work proposed will take advantage of the well-studied genetics of eye and coat color in the inbred mouse to address three specific aims: 1. To characterize the product of the pinkeyed-dilution locus with respect to its structure, synthesis, and subcellular distribution. The hypothesis that this protein serves to link the melanosomal membrane to melanin or the melanosomal matrix will be tested. 2. To test the hypothesis that interactions among the proteins encoded at the albino, brown, slaty and pinkeyed-dilution loci are critical in regulating ocular pigmentation. These interactions will be identified and their consequences upon the function and subcellular trafficking of these proteins will be defined. Subcellular fractionation, antipeptide antisera, biochemical separation techniques, assays of enzyme function and chemical analysis of melanin will be utilized to test this hypothesis. 3. To understand the pathogenesis of specific mutations (genetic diseases) which affect these proteins and thus reduce ocular pigmentation. The effects of defined mutations at these loci on the expression, function and subcellular distribution of their respective gene products and those of the other three proteins of interest in ocular melanocytes taken from inbred mice from birth through adulthood will be analyzed.