Muller glia and retina regeneration

描述(申请人提供)：尽管硬骨和哺乳动物的视网膜在结构和功能上相似，但哺乳动物的视网膜疾病或损伤会导致不可修复的视力丧失，而受伤的硬骨视网膜会产生再生反应，恢复失明的视力。成功再生的关键是Muller glia(MG)，它可以去分化并产生能够再生所有主要视网膜细胞类型的视网膜前体细胞。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，鱼类和哺乳动物再生反应的一个关键区别是MG在视网膜损伤后去分化的能力。我们认为，对MG去分化和产生增殖的视网膜前体细胞的机制的理解将为在哺乳动物MG中刺激这一过程提供新的策略。由于斑马鱼在视网膜损伤后会产生强大的再生反应，它们为揭示这些机制提供了一个有用的模型系统。这一建议侧重于揭示刺激MG去分化的分泌信号和受体，这些信号被传递到基因组的机制，以及MG来源的祖细胞增殖的潜在机制。此外，还建立了新的斑马鱼模型，以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弥补视网膜再生过程中MG的损失。这些研究将导致诱导哺乳动物MG脱分化和视网膜再生的新策略，可应用于修复受损或患病的人类视网膜。

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.