MECHANISMS OF RETINAL DEGENERATION

在果蝇中产生了大量的视网膜变性突变体。对这些突变体的分析已经确定了视觉转导级联的几个关键成分以及光感受器细胞的其他关键细胞生物学成分，这导致了潜在退化机制的模型。这个项目将使用分子、遗传和细胞生物学方法来研究与两个不同突变体相关的退化机制。显性视紫红质突变是人类一种常染色体显性遗传性视网膜色素变性的主要原因。已经提出了几种视网膜退化过程的机制。一类显性视紫红质突变体以前在果蝇中被鉴定，并被证明通过阻断野生型视紫红质蛋白的成熟而经历退化。我们分离出另外两个显性视紫红质突变(ineaEpp36和ineaEpp100)，它们表现为视网膜变性，但不阻碍视紫红质成熟。此外，几行数据有力地表明，ineaEpp36和ineaEpp100突变使用不同的机制来产生视网膜退行性变表型。我们将研究这些潜在的变性机制，以阐明常染色体显性遗传性视网膜色素变性的其他模型。视网膜变性G(RdgG)突变表现出一种光不依赖、温度敏感的视网膜变性表型。RdgG突变体的电生理光反应(通过视网膜电信号测量)是野生型的，除了在延长的饱和光刺激后无法恢复黑暗。这表明rdgG突变体可能表现出视觉转导过程中一个关键成分的“衰退”。

A large number of retinal degeneration mutants have been generated in Drosophila. Analyzing these mutants have identified several key components of the visual transduction cascade and other critical cell biological components for the photoreceptor cell, which has led to models for the underlying degeneration mechanisms. This project will employ molecular, genetic, and cell biological approaches to examine the degeneration mechanisms associated with two different mutants. Dominant rhodopsin mutations are a major cause of one form of autosomal dominant retinitis pigmentosa in humans. Several mechanisms have been proposed for the retinal degeneration process. One class of dominant rhodopsin mutants was previously characterized in Drosophila and shown to undergo degeneration by blocking the maturation of the wild-type rhodopsin protein. We isolated two additional dominant rhodopsin mutations (ninaEpp36 and ninaEpp100 that exhibit retinal degeneration, but do not block rhodopsin maturation. Additionally, several lines of data strongly suggest that the ninaEpp36 and ninaEpp100 mutations utilize different mechanisms to produce the retinal degeneration phenotype. We will examine these underlying degeneration mechanisms to elucidate additional models for autosomal dominant retinitis pigementosa. The retinal degeneration G (rdgG) mutation exhibits a light-independent, temperature-sensitive retinal degeneration phenotype. The electrophysiological light response (measured by the electroretinogram) of the rdgG mutant is wild-type, except for the inability to dark recover after an extended saturating light stimulus. This suggests that the rdgG mutant may exhibit "run-down" of a critical component in the visual transduction process.