STUDIES IN GLAUCOMATOUS OPTIC NERVE DAMAGE

描述（由申请人提供）：视网膜神经节细胞（RGC）存活率为 被认为取决于TrkB受体的激活水平， 内源性神经营养因子，BDNF和NT 4/5。这些神经营养因子（NT）是由 来自上级丘，并与特异性TrkB受体复合。他们 然后通过逆行轴突运输到达RCG细胞体。他们在那里行动 通过刺激特定的细胞存活途径来保护RGC， 抑制特定的细胞死亡途径（细胞凋亡）。 眼内压升高（IOP）是青光眼的主要危险因素， 阻碍轴突运输，并已显示出抑制NT向 RGC。此外，有充分的理由相信，其他风险因素， 青光眼，如年龄和以前的视神经损伤，也可能影响这一点， 系统，可能通过减少TrkB受体的产生， 或者两者都是。这些事实导致了这样的假设，在青光眼中，RGC死亡， 由神经营养因子依赖性TrkB的激活减少引起 介导的生存途径。 使用Brown Norway大鼠，现在存在用于建模慢性升高的方法。 眼压，手术降低眼压，并在老年人中研究这些现象，以及 年轻的成年动物这一建议将决定这三个方面的影响 影响神经营养因子TrkB激活的生存率的重要青光眼危险因素 信号通路和RGC存活。最后一个具体目标将 增强NT介导的细胞存活途径的活性， IOP控制后部分受损的眼睛。这是最常见的 青光眼的临床表现成功将通过衡量减少 RGC损失以及NT介导的信号通路的变化， 生存这些实验将有助于确定潜在的代理人 其增强RGC中TrkB活化作为青光眼的神经保护疗法。

DESCRIPTION (provided by applicant): Retinal ganglion cell (RGC) survival is thought to depend on the level of activation of TrkB receptors by the endogenous neurotrophins, BDNF and NT4/5. These neurotrophins (NT) are derived from the superior colliculus, and complex with specific TrkB receptors. They then travel by retrograde axonal transport to the RCG cell body. There they act to preserve RGC by stimulating specific cell survival pathways, and by inhibiting specific cell death pathways (apoptosis). Elevated intraocular pressure (IOP), a major risk factor for glaucoma, obstructs axonal transport, and has been shown to inhibit delivery of NT to the RGC. In addition, there is good reason to believe that other risk factors for glaucoma, such as aging and previous optic nerve damage, may also affect this system, possibly by reducing the production of TrkB receptors, the production of NT, or both. These facts lead to the hypothesis that, in glaucoma, RGC death results from a reduction in the activation of neurotrophin-dependent TrkB mediated survival pathways. Using Brown Norway rats, methods now exist for modeling chronically elevated IOP, surgically lowering IOP, and studying these phenomena in aged, as well as young adult animals. This proposal will determine the effects of these three important glaucoma risk factors on neurotrophin TrkB activated survival signaling pathways and on RGC survival. A final specific aim will pharmacologically enhance the activity of NT-mediated cell survival pathways in partially damaged eyes following IOP control. This models the most common clinical situation in glaucoma. Success will be gauged by measuring decreased RGC loss, as well as changes in NT-mediated signaling pathways that enhance survival. These experiments will help to determine the potential for agents that enhance TrkB-activation in RGCs as a neuroprotective therapy for glaucoma.