Muller glia and retina regeneration

描述（由申请人提供）：尽管硬骨鱼和哺乳动物视网膜之间的结构和功能相似，但哺乳动物视网膜的疾病或损伤导致不可修复的视力丧失，而受损的硬骨鱼视网膜产生恢复丧失的视力的再生反应。成功再生的关键是Muller胶质细胞（MG），它去分化并产生可以再生所有主要视网膜细胞类型的视网膜祖细胞。相比之下，哺乳动物MG对视网膜损伤的反应是伴随着肥大的反应性神经胶质增生;这些细胞很少重新进入细胞周期并再生新的神经元。这些数据表明，鱼类和哺乳动物的再生反应之间的关键区别是MG在视网膜损伤后去分化的能力。我们建议，MG去分化和产生视网膜祖细胞的增殖人口的机制的理解将提出新的策略，刺激这一过程中的哺乳动物MG。由于斑马鱼在视网膜损伤后会产生强大的再生反应，因此它们为揭示这些机制提供了有用的模型系统。该提案的重点是揭示刺激MG去分化的分泌信号和受体，这些信号传递到基因组的机制和MG衍生祖细胞增殖的机制。此外，已经建立了新的斑马鱼模型来测试任何视网膜细胞类型的消融是否足以诱导MG去分化和视网膜再生，以及是否有任何细胞可以补偿视网膜再生期间MG的损失。这些研究应导致新的策略，诱导MG去分化和视网膜再生的哺乳动物，可应用于修复受损或患病的人视网膜。

DESCRIPTION (provided by applicant): Despite structural and functional similarities between the teleost and mammalian retina, disease or injury of the mammalian retina leads to irreparable vision loss, while the injured teleost retina mounts a regenerative response that restores lost sight. Key to successful regeneration is Muller glia (MG), which dedifferentiate and generate retinal progenitors that can regenerate all major retinal cell types. In contrast, mammalian MG responds to retinal injury by reactive gliosis that is accompanied by hypertrophy; rarely do these cells re-enter the cell cycle and regenerate new neurons. These data suggest that a key difference between the regenerative responses of fish and mammals is the ability of MG to dedifferentiate following retinal injury. We propose that an understanding of the mechanisms by which MG dedifferentiate and generate a proliferating population of retinal progenitors will suggest novel strategies for stimulating this process in mammalian MG. Because zebra fish mount a robust regenerative response following retinal injury, they provide a useful model system for uncovering these mechanisms. This proposal focuses on uncovering secreted signals and receptors that stimulate MG dedifferentiation, mechanisms by which these signals are transmitted to the genome and mechanisms underlying proliferation of MG-derived progenitors. In addition, new zebra fish models have been created to test whether ablation of any retinal cell type is sufficient to induce MG dedifferentiation and retina regeneration and if any cells can compensate for loss of MG during retina regeneration. These studies should lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which can be applied to repairing a damaged or diseased human retina.