Neuronal Cell Cycle and Survival

描述（由申请人提供）：该研究涉及感光神经元如何永久退出细胞周期，以及细胞周期退出与神经变性和癌症的关系。提出了一种新的假设，认为细胞周期退出与感光神经元的轴突结构及其存活有关。果蝇黑腹果蝇的眼睛将被用来评估这一新的假设，并确定细胞周期进程的特定方面，或有丝分裂后结构，触发神经元丢失，以及寻找影响这些事件的新的未知基因。这些目标将通过使用转基因果蝇和分子遗传技术有条件地将rna和蛋白质靶向到特定的感光细胞亚群来实现。通过这种方式，细胞周期、细胞骨架和多种细胞死亡途径的组成部分将被操纵，以确定它们对细胞周期静止维持的影响，对光感受器细胞（尤其是轴突）结构的影响，以及对光感受器细胞存活的细胞自主和非自主机制的影响。本研究获得的信息有望指导减少视网膜母细胞瘤增殖的方法，最大限度地减少某些视网膜变性的神经元损失，并可能减少其他神经退行性疾病的神经元损失，如阿尔茨海默病、淀粉样萎缩性侧索硬化症、亨廷顿病、沙克-玛丽牙病、遗传性痉挛性截瘫SPG10、脊髓小脑共济失调5型、额颞叶痴呆、某些病毒性脑炎综合征、帕金森氏症和中风。

DESCRIPTION (provided by applicant): The research addresses how photoreceptor neurons withdraw permanently from the cell cycle, and the relationships of cell cycle withdrawal to both neural degeneration and to cancer. A new hypothesis is proposed that relates cell cycle withdrawal to the axonal structure of photoreceptor neurons, and to their survival. The eye of the fruit fly Drosophila melanogaster will be used to evaluate this new hypothesis, and to identify specific aspects of cell cycle progression, or of postmitotic structure, that trigger neuronal loss, as well as to search for novel, unknown genes that influence these events. These objectives will be achieved by using transgenic fruit flies and molecular genetic techniques to target RNAs and proteins to specific subsets of photoreceptor cells in a conditional manner. In this way, components of the cell cycle, cytoskeleton, and multiple cell death pathways will be manipulated to determine their effects on the maintenance of cell cycle quiescence, on the structure of photoreceptor cells and especially their axons, and on the cell-autonomous and non-autonomous mechanisms of photoreceptor cell survival. The information obtained in this study is expected to guide approaches to reduce proliferation of retinoblastoma, to minimize neuronal loss in some retinal degeneration, and possibly to reduce neuronal loss in other neurodegenerative conditions such as Alzheimer's Disease, Amylotrophic Lateral Sclerosis, Huntington's Disease, Charcot-Marie Tooth Disease, hereditary spastic paraplegia SPG10, Spinocerebellar Ataxia type 5, Fronto-temporal Dementia, certain viral encephalitis syndromes, Parkinson's Disease, and stroke. PUBLIC HEALTH RELEVANCE: The proposal explores a novel hypothesis connecting cell proliferation in the nervous system to nerve cell structure and to neuron degeneration. The studies make use of the eye of the fruit fly Drosophila melanogaster. The results will be useful for the design of new approaches to treating retinoblastoma, retinal degeneration, and neurodegenerative conditions.