Stimulation of retinal regeneration

描述(申请人提供)：像神经系统的其他区域一样，视网膜会受到许多后天和遗传性神经元退行性疾病的影响。由于视网膜为大脑提供了所有视觉感觉信息的输入，细胞的丧失会导致视力受损，并可能导致完全失明。许多视网膜退行性疾病只影响一部分视网膜细胞，尽管在更严重的疾病中，经常会发生整个视网膜的丢失和重组。长期以来，人们一直认为在人类中，退化的细胞不会恢复；然而，现在越来越多的证据表明，哺乳动物的视网膜再生神经元的能力有限，在非哺乳动物脊椎动物中发现的再生反应的一些成分也存在于哺乳动物中。在FISH中，所有类型的新神经元在视网膜损伤后从穆勒胶质细胞再生，它们在功能上整合到现有的电路中。在鸟类和啮齿动物中，再生受到相当大的限制，无论是在数量上还是在神经元类型上。尽管与冷血近亲相比，这可能代表了恒温脊椎动物的退化再生反应，但所有脊椎动物的视网膜中都存在穆勒胶质细胞，它是再生的细胞来源。我们最近发表的数据和新的未发表的初步数据表明，Muller胶质细胞的再生反应可能受到激活神经源性基因表达模式的抑制剂的限制。在这项提案中，我们概述了测试特定假设的实验，这些假设涉及限制哺乳动物视网膜中Muller胶质细胞再生的因素。这些实验的结果将使人们更好地了解哺乳动物Muller胶质细胞再生潜力的极限，并可能导致开发治疗人类视网膜变性的新策略。

DESCRIPTION (provided by applicant): 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. It has long been thought that in humans there is no recovery of the degenerated cells; however, there is now increasing evidence that the mammalian retina has a limited capacity for neuronal regeneration, and some components of the regenerative response found in non-mammalian vertebrates are also present in mammals. In fish, new neurons of all types regenerate from Muller glia following retinal damage and they are functionally integrated into the existing circuitry. Regeneration is considerably more limited in birds and rodents, both in quantity and types of neurons generated. Although this may represent a vestigial regenerative response in homoeothermic vertebrates when compared with their cold- blooded relatives, Muller glia, the cellular source for regeneration, are present in all vertebrate retinas. Our recently published data and new preliminary unpublished data indicate that the regenerative response of Muller glia might be limited by inhibitors in their activation of a neurogenic pattern of gene expression. In this proposal we outline experiments to test specific hypotheses about the factors that limit regeneration from the Muller glia in the mammalian retina. The results of these experiments will provide a better understanding of the limits of the regenerative potential of mammalian Muller glia, and may lead to development of novel strategies for treatment of human retinal degeneration.