Cell Death Pathways in Glaucomatous Neurodegeneration

青光眼的视力丧失是由视网膜的输出神经元，即视网膜神经节细胞的死亡引起的。 虽然目前还不清楚青光眼中视网膜神经节细胞是如何受损的，但有相当多的数据支持 轴突损伤是青光眼早期的一种严重侮辱。事实上，人们认为视网膜神经节细胞轴突受到了损伤 因为它们通过一种叫做筛板的特殊结构离开眼睛。尽管知道可能的位置 在青光眼损害中，视网膜神经节细胞对高眼压的最早病理反应 都是未定义的。也许并不令人惊讶的是，这些事件很难定义，因为病理 反应可能只在轴突的一小部分被短暂激活(当它们穿过板层时)， 而且在任何给定的时间只存在于轴突的一个子集中。我们和其他人已经证明，在轴突侮辱之后， 分子通路控制着不同视网膜神经节细胞的退行性变。然而，我们并没有 了解非常局部的轴突损伤反应如何不可逆转地激活索马体和轴突退行性变程序。 在这里，我们描述的实验将定义控制和连接 视网膜神经节细胞对高眼压刺激的分区反应。我们的中心假设是 高眼压激活轴突损伤信号通路，调节脑室特异性 退化过程，抑制这些过程将防止青光眼神经退化。为了测试 在这一假设下，我们将在青光眼高眼压模型中扰动这些通路，并评估 对胞体和轴突变性的影响。此外，我们将研究抑制这些途径是如何改变的 视网膜神经节细胞损伤反应的关键方面，包括轴突运输和视网膜神经节细胞功能。 此外，我们还将定义视网膜神经节细胞内导致高眼压的转录变化- 诱导视网膜神经节细胞死亡。总体而言，这些实验将提供对 控制青光眼神经变性的病理信号。考虑到轴突侮辱的重要性 青光眼中的轴突变性，这些实验可能会确定新的开发靶点 青光眼的神经保护性治疗。

Vision loss in glaucoma is caused by the death of the output neurons of the retina, the retinal ganglion cells. While it is unclear how retinal ganglion cells are injured in glaucoma, there are considerable data supporting axonal injury as an early, critical insult in glaucoma. In fact, it is thought that retinal ganglion cell axons are injured as they exit the eye through a specialized structure called the lamina cribrosa. Despite knowing the likely location of the glaucomatous insult, the earliest pathological responses to ocular hypertension within retinal ganglion cells are undefined. It is perhaps not surprising that these events have been difficult to define because the pathological responses are likely activated only transiently, in a small region of the axon (as they travel through the lamina), and only in a subset of axons at any given time. We and others have shown that after an axonal insult, distinct molecular pathways control degeneration of different retinal ganglion cell compartments. However, we do not know how a very local axonal injury response irreversibly activates somal and axonal degenerative programs. Here, we describe experiments that will define the molecular pathways controlling and linking the compartmentalized response of retinal ganglion cells to an ocular hypertensive insult. Our central hypothesis is that ocular hypertension activates axonal injury signaling pathways that regulate compartment-specific degeneration processes, and inhibiting these processes will prevent glaucomatous neurodegeneration. To test this hypothesis, we will perturb these pathways in ocular hypertensive models of glaucoma and assess the effects on somal and axonal degeneration. Furthermore, we will examine how inhibiting these pathways alters key aspects of retinal ganglion cell injury response, including axonal transport and retinal ganglion cell function. Also, we will define the transcriptomic changes within retinal ganglion cells that contribute to ocular hypertension- induced retinal ganglion cell death. Overall these experiments will provide an integrated understanding of the pathological signaling that controls glaucomatous neurodegeneration. Given the importance of axonal insult and axonal degeneration in glaucoma, these experiments will likely identify novel targets for developing neuroprotective treatments for glaucoma.