Induction and characterization of RGC axon regeneration in a mouse model of glaucoma

小鼠青光眼模型视网膜节细胞轴突再生的诱导及特征 青光眼是一大群不同种类的视神经疾病，其特征是 导致不可逆转的视力丧失的视神经变性。原发性开角型青光眼 青光眼(POAG)是最常见的青光眼，占所有病例的大多数。 眼压升高是最重要的，也是唯一已知的可改变的危险因素。 与POAG有关。尽管通过治疗降低了眼压，但视力损失仍在继续 大多数青光眼患者的进展。 视网膜神经节细胞(RGC)是唯一传递视觉信息的神经元。 视网膜进入大脑。像中枢神经系统中的其他神经元一样，视网膜节细胞不 受损后会自发再生轴突。这些神经元共同构成了 视神经，在轴突受损时也非常脆弱。而分子 青光眼中损害视网膜节细胞的途径尚不完全清楚，几项研究使用 青光眼的动物模型描述了视神经在青光眼的 板层水平，RGC轴突离开眼睛的地方。此外，在青光眼的小鼠模型中 (即地塞米松诱导的高眼压(OHT))，已证实视神经 变性先于视网膜节细胞的结构和功能丧失，轴突损伤和 运输缺陷始于视神经头。重要的是，对RGC轴突的侮辱 这些情况最终会导致损伤部位远端的沃勒变性 导致视网膜和大脑之间的连接中断。 在老鼠身上使用视神经挤压，我们和其他人已经证明了基因 在视网膜节细胞中操纵不同的基因可以促进远距离轴突再生。 然而，虽然外伤性视神经挤压是一种有用的技术来研究 RGC轴突再生的机制，它不能忠实地复制青光眼视神经 神经损伤是部分的轴突损伤，随着时间的推移逐渐发展。在这 提案中，我们将结合轴突追踪技术、小鼠遗传学和3D成像 观察RGC轴突再生和轴突重塑发生的程度。 啊哈。从这项研究中获得的结果将在我们调查的方式上产生范式转变 视神经再生，为今后的研究开发提供了基础 晚期青光眼患者的修复性治疗。

Induction and characterization of RGC axon regeneration in a mouse model of glaucoma Glaucoma is a large and heterogeneous group of optic neuropathies characterized by optic nerve degeneration that results in irreversible vision loss. Primary open-angle glaucoma (POAG) is the most common form of glaucoma, accounting for the majority of all cases. Elevated intraocular pressure (IOP) is the most important and only known modifiable risk factor associated with POAG. Despite therapeutic reduction of IOP, vision loss still continues to progress in most glaucoma patients. Retinal ganglion cells (RGCs) are the only neurons that relay visual information from the retina to the brain. Like other neurons in the central nervous system, RGCs do not spontaneously regenerate their axons after damage. These neurons, which collectively form the optic nerve, are also highly vulnerable when their axons are damaged. While the molecular pathways that damage RGCs in glaucoma are not fully understood, several studies using the animal models of glaucoma have described the presence of local insult in the optic nerve at the level of lamina, where the RGC axons exit the eye. Furthermore, in a mouse model of glaucoma (i.e. dexamethasone-induced ocular hypertension (OHT)), it was demonstrated that optic nerve degeneration precedes structural and functional loss of RGCs, and that the axonal damage and transport deficits initiate at the optic nerve head. Importantly, insults to the RGC axons under these circumstances result in Wallerian degeneration distal to the site of damage, ultimately causing disconnection between the retina and the brain. Using optic nerve crush in mice, we and others have demonstrated that genetic manipulation of different genes in the RGCs promotes long distance axon regeneration. However, while traumatic optic nerve crush is a useful technique for investigating the mechanisms of RGC axon regeneration, it does not faithfully reproduce glaucomatous optic nerve damage which axonal injury is partial and progresses gradually over time. In this proposal, we will use a combination of axon tracing techniques, mouse genetics and 3D imaging to examine the extent to which RGC axon regeneration and axon remodeling takes place after OHT. The results obtained from this study will create a paradigm shift in how we investigate optic nerve regeneration, and provide foundation for future investigations into developing reparative therapy for treating advanced glaucoma patients.