GENETIC ANALYSIS OF RETINAL DEGENERATION

视网膜变性的遗传分析

• 批准号: 2160976
• 负责人: JOSEPH E O'TOUSA
• 金额: $ 21.23万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2160976
• 关键词: GENETIC; ANALYSIS; RETINAL; DEGENERATION

Specific genetic defects are responsible for a large percentage of the retinal diseases that afflict human populations. The long range goal of this research program is to characterize analogous genetically inherited retinal degeneration syndromes in the invertebrate, Drosophila, to better understand the molecular basis of degenerative retinal diseases. During previous grant periods, we determined the molecular basis of four inherited retinal degeneration syndromes in Drosophila. This proposal is focused on the cellular mechanisms by which mutations in one of these genes, rhodopsin, causes retinal disease. Rhodopsin mutations are known to cause retinal degeneration in humans, other vertebrates, and in Drosophila. In most known cases, including the Drosophila mutants we will study, the mutant rhodopsin acts in a dominant fashion to trigger degeneration. Also, the Drosophila mutants share the property with the majority of human mutant genes that they appear to disrupt the posttranslational maturation pathway. The experiments proposed here will investigate the cellular mechanisms and additional gene products involved in rhodopsin maturation and recycling. The project is organized into four specific aims: (1) To examine the dominant nature of certain Drosophila rhodopsin mutants. We will use histological markers to examine the fate of the mutant protein in photoreceptors, determine the effect of the mutant rhodopsin on other membrane proteins, and develop a genetic screen for additional genes required for rhodopsin maturation (2) To identify additional molecular components involved in rhodopsin maturation. Gene products required for membrane protein maturation through the endoplasmic reticulum/Golgi complex and for post-Golgi transport of rhodopsin will be characterized. We will analyze mechanisms involved in rhodopsin transport to the photosensitive membranes and retinal degeneration B protein transport to the specialized endoplasmic reticulum membranes of the photoreceptor. (3) To analyze the enzymatic regulation and substrate specificity of the retinal degeneration C (rdgC) gene. Rhodopsin is thought to be a substrate of the rdgC phosphatase. We will characterize the enzymatic activity of the rdgC protein and analyze mutants of rdgC exhibiting altered regulation. (4) To characterize two gene products required rhodopsin maturation already identified by mutation. These genes are required to generate high levels of rhodopsin, probably by promoting efficient utilization of vitamin A. We will determine if these ones encode proteins that act in photoreceptors, and if so, determine the molecular nature of the encoded gene.

特定的遗传缺陷是造成大部分 折磨人类的视网膜疾病。长期目标是 这项研究计划是描述类似的遗传 无脊椎动物果蝇的视网膜变性综合症 更好地了解视网膜变性疾病的分子基础。 在以前的资助期间，我们确定了四种分子基础， 果蝇遗传性视网膜变性综合征这项建议 集中在细胞机制上， 基因，视紫红质，导致视网膜疾病。视紫红质突变是已知的 导致人类和其他脊椎动物视网膜退化， 果蝇在大多数已知的情况下，包括果蝇突变体， 将研究，突变的视紫红质的行为在一个主导的方式，以触发 退化同样，果蝇突变体与 大多数人类突变基因，他们似乎破坏了 翻译后成熟途径。这里提出的实验将 研究细胞机制和其他基因产物 参与视紫红质的成熟和再循环。该项目是组织 分为四个具体目标： (1)研究某些果蝇视紫红质的优势性质 变种人我们将使用组织学标记来检查 光感受器中的突变蛋白，确定突变体的作用 视紫红质对其他膜蛋白，并开发一个遗传筛选， 视紫红质成熟所需的其他基因 (2)为了鉴定与视紫红质有关的其他分子成分 成熟膜蛋白成熟所需的基因产物 通过内质网/高尔基体复合体和后高尔基体 将表征视紫红质的转运。我们将分析机制 参与视紫红质向光敏膜的运输， 视网膜变性B蛋白转运至特化内质网 感光器的网膜。 (3)为了分析该酶的酶促调节和底物特异性， 视网膜变性C（rdgC）基因。视紫红质被认为是一种 rdgC磷酸酶的底物。我们将描述酶的特性 rdgC蛋白的活性，并分析表现出 改变规则。 (4)为了表征视紫红质成熟所需的两种基因产物， 已经通过突变识别出来了。这些基因是产生 高水平的视紫红质，可能是通过促进有效利用 维生素A我们将确定这些基因编码的蛋白质 在光感受器，如果是这样，确定分子的性质， 编码基因