Stimulation of Retinal Regeneration

摘要 目前，没有有效的治疗方法来替代视网膜神经元丢失患者的变性神经元 从退行性疾病，如发生在青光眼和黄斑变性患者。相比之下， 非哺乳类脊椎动物，如鱼类和两栖动物的视网膜， 视网膜损伤后。视网膜受伤后，鱼Muller Glia会产生所有不同类型的视网膜 神经元来取代那些丢失的神经元。在理解分子生物学方面已经取得了相当大的进展， 非哺乳类脊椎动物的再生机制，如果这些知识可以应用于人类， 这可能会导致为视力受损患者开发新型再生疗法。五 几年前，我们发现通过表达一个关键的前神经调节基因，称为Ascl 1， 我们可以诱导它们在受伤后再生新的神经元。小鼠体内新再生的神经元 视网膜与现有的未受损的神经元连接起来，并开始发挥功能。这些结果表明， 第一次，功能性神经元再生是可能的哺乳动物，像我们自己;然而，我们已经发现， 可能需要额外的因素来引导再生到适当类型和数量的神经元 需要针对具体疾病。在这个提议中，我们的目的是更好地定义特定的转录因子 最好的再生每一个主要的视网膜神经元类型的组合。我们还建议确定 由Muller神经胶质再生的神经元的类型是否受视网膜损伤的类型的影响，以及 这一过程是否可以有效地恢复视网膜病变动物模型的功能性视力， 退化最后，我们建议进行研究，以更好地了解可以利用的信号通路。 以进一步指导MG介导的再生过程。在五年结束时，我们预计将有更多的 在治疗视网膜疾病和创伤方面，完善了再生的潜力。

Abstract Currently, there are no effective therapies to replace degenerated neurons in patients with retina neuron loss from degenerative diseases, such as occurs in patients with glaucoma and macular degeneration. By contrast, retinas of non-mammalian vertebrates, such as fish and amphibians, show a robust regenerative response following retinal damage. Upon injury to the retina, fish Muller Glia generate all different types of retinal neurons to replace those that were lost. There has been considerable progress in understanding the molecular mechanisms of regeneration in non-mammalian vertebrates, and if this knowledge could be applied to humans, it might lead to the development of new types of regenerative therapies for patients with impaired vision. Five years ago, we discovered that by expressing a key proneural regulatory gene, called Ascl1, in the Muller glia of mice, we can induce them to regenerate new neurons after injury. The new regenerated neurons in the mouse retinas wired up with the existing, undamaged neurons and became functional. These results showed for the first time that functional neuron regeneration is possible in mammals, like ourselves; however, we have found that additional factors are likely required to guide the regeneration to the proper types and numbers of neurons needed to address specific diseases. In this proposal, our aim is to better define the specific transcription factor combinations that best regenerate each of the major retinal neurons types. We also propose to determine whether the types of neurons regenerated by the Muller glia are influenced by the type of retinal injury, and whether the process can be made efficient enough to restore functional vision in animal models of retinal degeneration. Lastly, we propose studies to better understand the signaling pathways that could be harnessed to further direct the MG-mediated regeneration process. At the end of five years, we expect to have further refined the potential for regeneration in the treatment of retinal disease and trauma.