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

小鼠青光眼模型视网膜神经节细胞轴突再生的诱导和鉴定 青光眼是一种大而异质的视神经病变，其特征在于： 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 原发性开角型青光眼（POAG）是青光眼最常见的形式，占所有病例的大多数。 眼内压升高（IOP）是最重要的，也是唯一已知的可改变的风险因素 与POAG有关。尽管治疗性降低了IOP，但视力丧失仍然持续， 大多数青光眼患者的进展。 视网膜神经节细胞（RGC）是唯一从视网膜传递视觉信息的神经元。 视网膜到大脑像中枢神经系统中的其他神经元一样，RGC不 它们的轴突会在受损后自发再生这些神经元共同组成了 视神经轴突受损时也非常脆弱。同时分子 青光眼中损害RGC的途径尚未完全了解，一些研究使用 青光眼的动物模型已经描述了在视神经中存在局部损伤 层的水平，其中RGC轴突退出眼睛。此外，在青光眼小鼠模型中， (i.e.地塞米松诱导的高眼压（OHT）），表明视神经 变性先于RGC的结构和功能丧失，并且轴突损伤和 运输缺陷起始于视神经头。重要的是，对RGC轴突的损伤在 这些情况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 我们和其他人通过对小鼠的视神经挤压实验，证明了基因 在RGC中操纵不同的基因促进长距离轴突再生。 然而，虽然创伤性视神经挤压是一种有用的技术，用于调查 RGC轴突再生的机制，它不能忠实地再现青光眼视神经 轴突损伤是部分的并且随着时间的推移逐渐进展的神经损伤。在这 我们将结合轴突追踪技术、小鼠遗传学和3D成像技术， 检查RGC轴突再生和轴突重塑发生的程度， 好的。从这项研究中获得的结果将创造一个范式转变，我们如何调查 视神经再生的研究，为今后的研究提供基础， 用于治疗晚期青光眼患者的修复疗法。

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.