Stimulation of Retinal Regeneration

摘要 好了！ 像神经系统的其他区域一样，视网膜受制于许多后天和遗传的神经元。 退行性疾病。由于视网膜为大脑提供所有视觉感觉信息的输入，因此 细胞丢失会导致视力受损，并有可能导致完全失明。许多视网膜退行性变 疾病只影响一小部分视网膜细胞，尽管在更晚期的疾病中，往往会出现视网膜细胞的丢失和 可以发生整个视网膜的重组。在哺乳动物中，大脑的再生能力非常有限 退化的细胞；然而，在FISH中，所有类型的新神经元都是从以下Müler胶质细胞(MG)再生的 视网膜损伤，它们在功能上集成到现有的电路中。虽然哺乳动物，包括 缺乏这种能力的人，MG，再生的细胞来源，存在于所有脊椎动物的视网膜中。我们 假设哺乳动物MG的再生是有限的，因为它们不能表达原神经 损伤后基因表达的程序。我们发现病毒过度表达的一种神经原 在体外，转录因子可以部分地将哺乳动物MG重新编程为神经性状态。用于活体内 证实，我们获得了一只在MG中表达Ascl1的转基因小鼠。当我们诱导Ascl1 Ascl1和组蛋白脱乙酰酶(HDAC)抑制可刺激成年MG的表达 成年小鼠NMDA损伤后MG新神经元的产生。MG来源的神经元 主要类似于双极细胞或无长突细胞，并与现有的视网膜回路形成连接。这些 结果首次表明，在成年哺乳动物的视网膜上可以再生有功能的神经元。 适当地集成到现有的主机电路中，但提出一个关键问题：为什么MG只生产 双极细胞和无长突细胞？在这项提案中，我们概述了研究，以更好地理解，并潜在地 克服哺乳动物视网膜再生的障碍。 好了！

Abstract ! Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since the retina provides the input for all visual sensory information to the brain, the loss of cells results in visual impairment and potentially complete blindness. Many retinal degenerative diseases affect only a subset of the retinal cells, although, frequently in more advanced disease, loss and reorganization of the entire retina can occur. In mammals, there is very limited regeneration of the degenerated cells; however, in fish, new neurons of all types regenerate from Müller glia (MG) following retinal damage and they are functionally integrated into the existing circuitry. Although mammals, including people, lack this ability, MG, the cellular source for regeneration, are present in all vertebrate retinas. We hypothesize that regeneration from mammalian MG is limited because they fail to express the proneural program of gene expression after injury. We have found that viral over-expression of a proneural transcription factor can partly reprogram mammalian MG to a neurogenic state in vitro. For in vivo confirmation, we generated a transgenic mouse to express Ascl1 in MG. When we induce Ascl1 expression in adult MG, the combination of Ascl1 and histone deacetylase (HDAC) inhibition can stimulate new neuron production from MG in adult mice after NMDA induced damage. The MG-derived neurons primarily resemble bipolar or amacrine cells, and form connections with the existing retinal circuitry. These results show for the first time that functional neurons can be regenerated in an adult mammalian retina and properly integrate within the existing host circuit, but raise a key question: Why do the MG only produce bipolar cells and amacrine cells? In this proposal we outline studies to better understand, and potentially overcome, the barriers to regeneration in mammalian retina. !