The role of the bHLH transcription factor NeuroD in regulating photoreceptor rege

描述（由申请人提供）：光感受器退行性疾病导致人类永久性视力丧失。开发恢复人类视力的再生疗法将需要对目前对基于干细胞的再生机制的理解取得实质性进展。我们研究的长期目标是以斑马鱼为模型生物，了解视网膜中基于干细胞的神经元再生的分子机制。实现这一目标的下一步，以及本研究的总体目标，是识别NeuroD在感光细胞再生中的作用。这一目标将通过测试的核心假设，NeuroD是一个关键分子的信号通路，控制感光细胞再生。该假设将通过实现2个特定目标进行检验。具体目标1将检验以下具体假设：1）NeuroD是感光细胞祖细胞在感光细胞再生期间退出细胞周期所必需的，2）NeuroD功能通过感光细胞再生所必需的下游基因介导。这将通过比较正常和NeuroD缺陷视网膜之间的感光细胞再生、细胞增殖和再生视网膜中下游基因的表达来实现。具体目标2将测试特定假设，即NeuroD在感光细胞再生期间介导感光细胞祖细胞中的经典Wnt信号传导的功能。这将通过比较neuroD的表达和典型Wnt效应子的定位来实现（？连环蛋白），并确定经典Wnt信号传导操纵对neuroD表达的影响。这项研究将为理解脊椎动物中调节感光细胞再生的途径提供重要而重要的一步，并将有助于我们对神经系统中调节干细胞再生的因素的基础知识。这一贡献将提供关键信息适用于发展再生疗法，旨在治疗人类视网膜疾病。

DESCRIPTION (provided by applicant): Photoreceptor degenerative diseases lead to permanent vision loss in humans. The development of regenerative therapies that restore vision in humans will require substantial advances to the current understanding of mechanisms of stem cell-based regeneration. The long-term goal of our research is to understand the molecular mechanisms that govern stem cell-based neuronal regeneration in the retina, using zebrafish as a model organism. A next step in achieving this goal, and the overall objective of the present research, is to discern the role of NeuroD in photoreceptor regeneration. This objective will be accomplished by testing the central hypothesis that NeuroD is a key molecule in signaling pathways that control photoreceptor regeneration. This hypothesis will be tested by accomplishing 2 specific aims. Specific Aim 1 will test the specific hypotheses that 1) NeuroD is required for photoreceptor progenitors to exit the cell cycle during photoreceptor regeneration and 2) NeuroD function is mediated via downstream genes that are essential for photoreceptor regeneration. This will be accomplished by comparing photoreceptor regeneration, cell proliferation, and expression of downstream genes in regenerating retinas between normal and NeuroD-deficient retinas. Specific Aim 2 will test the specific hypothesis that NeuroD mediates the function of canonical Wnt signaling in photoreceptor progenitors during photoreceptor regeneration. This will be accomplished by comparing neuroD expression and localization of the canonical Wnt effector (?-catenin), and determining the effects of canonical Wnt signaling manipulation on neuroD expression. This research will provide a significant and important step toward understanding pathways regulating photoreceptor regeneration in vertebrates, and will contribute to our fundamental knowledge of factors regulating stem cell-based regeneration in the nervous system. This contribution will provide critical information applicable to the development of regenerative therapies aimed at treating human retinal disease.