Autophagy and Retinal Ganglion Cell Death in Glaucoma

摘要 青光眼是一组疾病，是全世界永久性失明的第二大原因，其特点是 RGC轴突的慢性变性和视网膜神经节细胞(RGC)的进行性丢失，导致 视野缺陷和视力丧失。眼压升高是最广为人知的因素。 与青光眼的发生和发展有关。目前还没有提供神经保护的治疗方法 青光眼。目前的青光眼治疗方法旨在降低眼压，但无法挽救视网膜节细胞。更好的 青光眼RGC死亡和轴突变性的确切分子机制研究 对神经保护性治疗的发展至关重要。 自噬是一种溶酶体的降解过程，它通过消除 破坏细胞器和蛋白质。除了在维持细胞和组织动态平衡方面发挥关键作用外， 自噬被认为是一种生存途径，参与了应激诱导的适应。脑部功能障碍 自噬途径与越来越多的人类疾病有关，特别是与年龄有关的疾病。 疾病，以及几种神经退行性疾病。矛盾的是，在神经组织中，自噬起了作用 在神经保护以及神经元损伤和死亡中的重要作用取决于环境。 虽然不是广泛的，但青光眼背景下的自噬已经被独立的 实验室使用不同的实验模型。虽然所有的研究都同意自噬在 RGC对于损伤或高眼压的反应，对于自噬是促进生存还是 引发细胞死亡。最新的研究似乎表明，自噬的保护或致死作用依赖于 最初的损伤(即创伤性侮辱与眼压升高)。此外，自噬似乎在这一过程中扮演着不同的角色 RGC死亡和轴突变性。 这项拨款申请的目的是研究自噬对细胞凋亡的独立贡献。 急性青光眼和慢性高血压青光眼模型中RGC死亡和轴突变性。 为此，我们将使用我们实验室产生的独特工具，包括我们独特的DBA/2J转基因小鼠 基础自噬上调和缺乏的青光眼模型。我们期待着这一项目完成 将有助于进一步了解自噬在青光眼神经变性中的作用。多数 重要的是，我们的研究有可能为眼科疾病的治疗确定新的治疗靶点。 高血压和青光眼。

ABSTRACT Glaucoma is a group of diseases, second leading cause of permanent blindness worldwide, characterized by the chronic degeneration of RGC axons and progressive loss of retinal ganglion cells (RGCs), which results in visual field defects and vision loss. Elevated intraocular pressure (IOP) is the best-well known factor contributing to the onset and progression of glaucoma. There are not therapeutic treatments to offer neuroprotection in glaucoma. Current glaucoma therapies are directed at lowering IOP, but cannot rescue RGCs. A better understanding of the exact molecular mechanisms triggering RGC death and axonal degeneration in glaucoma is essential for the development of neuroprotective treatments. Autophagy is a lysosomal degradative process, which plays a central role in cellular homeostasis by eliminating damage organelles and proteins. In addition to having a key role on maintaining cellular and tissue homeostasis, autophagy is regarded as a survival pathway, involved in stress-induced adaptation. Dysfunction of the autophagy pathway has been associated to a growing number of human diseases, in particular age-related diseases, as well as to several neurodegenerative disorders. Paradoxically, in the neural tissue, autophagy plays an important role in neuroprotection as well as neuronal injury and death depending on the circumstances. Although not extensively, autophagy within a context of glaucoma, has been investigated by independent laboratories using different experimental models. While all of the studies agree that autophagy is activated in RGC in response to injury or elevated IOP, there is no consensus on whether autophagy promotes survival or triggers cell death. Latest studies seem to suggest that a protective or pro-death role of autophagy depend on the initial injury (i.e traumatic insult vs IOP elevation). Moreover, autophagy seems to have a different role in RGC death and axonal degeneration. The purpose of this grant application is to investigate the independent contribution of autophagy to apoptotic RGC death and axonal degeneration in acute injury and chronic hypertensive experimental models of glaucoma. For this, we will use unique tools generated in our laboratory, including our unique DBA/2J transgenic mouse glaucoma models with upregulated and deficient basal autophagy. We anticipate that completion of this project will contribute to a further understanding of the role of autophagy in neurodegeneration in glaucoma. Most importantly, our studies have the potential of identifying a novel therapeutic target for the treatment of ocular hypertension and glaucoma.