Genetic Analysis of Retinal Degeneration

描述(申请人提供)：视网膜退化是由大量光感受器表达的基因突变引发的。鉴于这些基因的生化作用的多样性，每个突变体必须对光感受器细胞生物学产生不同的主要影响。值得注意的是，遗传损伤的多样性通过相似的形态标志导致视网膜退化，这表明有可能发生共同的细胞死亡事件。在之前的授予周期中，成功地采用了一种无偏见的方法来识别在这些视网膜退化过程中起作用的基因。在用于视觉研究的实验动物中，这种方法只在果蝇身上可行。值得注意的是，该方法暗示了非caspase依赖的细胞死亡途径是视网膜疾病进展的关键组成部分。这项提议的三个目标侧重于分析这些途径的已确定的分子成分。它们在退化过程中的作用将通过遗传学、细胞生物学和分子方法相结合的方法来研究。这一努力有望为控制视网膜变性的细胞机制提供新的信息。因此，该提案解决了2004年国家眼科研究所发布的国家计划的主要目标之一。这项五年计划包括，在视网膜疾病类别中，“确定遗传性和视网膜退行性疾病所涉及的基因，并确定这些突变引发的疾病进展的病理生理机制。”

DESCRIPTION (provided by applicant): Retinal degeneration is triggered by mutations in a large number of photoreceptor-expressed genes. Given the diversity of biochemical roles of these genes, each mutant must have distinct primary effects on photoreceptor cell biology. It is remarkable that the diversity of genetic insults result in retinal degeneration via similar morphological landmarks, suggesting the possibility of shared cell death events. During the previous granting cycle, an unbiased approach was successfully employed to identify genes that act in these retinal degeneration processes. Among experimental animals used in vision research, this type of approach is feasible only in Drosophila. Significantly, the approach has implicated non-caspase dependent pathways of cell death as the critical component in the progression of retinal disease. The three aims of this proposal focus on the analysis of identified molecular components of these pathways. Their role in the degeneration process will be studied by a combination of genetic, cell biological and molecular approaches. The effort is expected to provide new information on the cellular mechanisms controlling retinal degeneration. Thus, the proposal addresses one of the major goals of the National Plan released by the National Eye Institute in 2004. This five year plan includes, in the category of retinal disease, to "identify the genes involved in both inherited and retinal degenerative diseases and determine the pathophysiological mechanisms underlying the disease progression triggered by these mutations."