Stimulation of retinal regeneration

描述（由申请人提供）：像神经系统的其他区域一样，视网膜容易受到许多获得性和遗传性神经退行性疾病的影响。由于视网膜为大脑提供了所有视觉感官信息的输入，细胞的损失会导致视觉障碍，甚至可能完全失明。许多视网膜退行性疾病只影响视网膜细胞的一个子集，尽管在更严重的疾病中，整个视网膜的损失和重组经常发生。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，哺乳动物视网膜的神经元再生能力有限，而且在非哺乳动物脊椎动物中发现的一些再生反应成分也存在于哺乳动物中。在鱼类中，所有类型的新神经元在视网膜损伤后从Muller胶质细胞再生，并在功能上整合到现有的电路中。在鸟类和啮齿动物中，再生的神经元数量和类型都相当有限。虽然与冷血动物相比，这可能代表了恒温脊椎动物的退化再生反应，但Muller胶质细胞作为再生的细胞来源，存在于所有脊椎动物的视网膜中。我们最近发表的数据和新的初步未发表的数据表明，Muller胶质细胞的再生反应可能受到神经源性基因表达模式激活抑制剂的限制。在本提案中，我们概述了实验，以测试有关限制哺乳动物视网膜Muller胶质细胞再生因素的特定假设。这些实验结果将更好地了解哺乳动物Muller胶质细胞再生潜力的局限性，并可能导致治疗人类视网膜变性的新策略的发展。

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 Our recently published data and new preliminary unpublished data indicate that the regenerative response of Muller glia might be limited by inhibitors in their activation of a neurogenic pattern of gene expression.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. PUBLIC HEALTH RELEVANCE: Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since regeneration of new retinal neurons does not occur in people, these diseases can leave them with permanent visual impairment. In this proposal we outline experiments to provide a better understanding of the limits of the regenerative potential of mammalian Muller glia, which may lead to development of novel strategies for treatment of human retinal degeneration.