PATHOGENESIS OF OCULAR ALBINISM

黑色素保护眼睛免受太阳辐射的伤害。 遗传性疾病，如白化病，会减少眼睛的色素沉着， 与严重的发病率相关。拟议研究的目标 是在分子水平上理解特定基因的功能 涉及黑色素合成和包装的产品，以及 影响眼部色素沉着的遗传性疾病的发病机制 皮肤，导致眼皮肤白化。眼睛是一种理想的系统 解决这些问题是因为高度集中的 眼组织中的黑素细胞与眼部色素沉着的关系 在一个可预测的出生后时间过程中。拟议的工作将需要 眼部和毛色遗传在近交系中的优势 鼠标来解决三个具体目标： 1.刻画微调稀释轨迹的乘积 到它的结构、合成和亚细胞分布。假说 这种蛋白质将黑素小体的膜与黑色素或 将对黑素小体基质进行检测。 2.为了检验这样一种假设，即编码在 白化、棕色、板条状和粉纹稀释基因座在 调节眼部色素沉着。这些相互作用将被识别并 它们对这些细胞的功能和亚细胞贩运的影响 蛋白质将被定义。亚细胞分级，抗肽 抗血清，生化分离技术，酶功能和 黑色素的化学分析将被用来检验这一假说。 3.了解特定突变(遗传病)的发病机制 它们会影响这些蛋白质，从而减少眼睛的色素沉着。这个 这些基因座明确突变对基因表达、功能和基因表达的影响 它们各自基因产物的亚细胞分布及其基因产物 眼部黑素细胞中的其他三种感兴趣的蛋白质 近亲交配的小鼠从出生到成年都将被分析。

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.