Molecular Analysis of Retinal Ganglion Cell Death

项目摘要/摘要 青光眼是一种由于视网膜神经节死亡而导致视野丧失的疾病。 细胞。尽管眼压升高仍然是青光眼最明确的危险因素，但它是 越来越清楚的是，广泛的其他因素也可以导致神经节细胞丢失。药理或 手术调节眼压可以使许多患者稳定下来，但对一些患者来说仍然是进行性的 失明。因此，迫切需要开发新的合理策略来减缓或防止神经元丢失。 发生在青光眼中。 有大量证据表明，眼睛像中枢神经系统的其他区域一样，含有内源性 神经营养/神经保护因子，其功能是限制细胞损伤。这项提议的基本前提是 这些神经保护机制可以被用来防止与以下相关的大部分细胞死亡 青光眼等疾病。这项提议关注的是一种神经保护分子，CNTF，一种具有 已经被证明在包括视网膜在内的许多中枢神经系统区域具有强大的神经保护作用 是减缓神经节细胞丢失进程的主要候选者。 在我们的初步数据中，我们提出了CNTF支持纯化的大鼠视网膜神经节细胞在 低密度培养及其下游效应子STAT3可防止视网膜神经节细胞在缺血时退化。 再灌注损伤。我们现在提出一系列实验，以测试是否可以防止RGC在 CNTF检测到谷氨酸的毒性水平。在第一个目标中，我们将定义CNTF使用的路径 发挥其保护作用。第二，我们将研究Müller胶质细胞是否能对CNTF做出反应并提供 分泌额外的神经保护因子或其他一系列因素对视网膜节细胞的协同保护作用 回应。最后，我们将测试CNTF激活的保护通路是否会导致 线粒体解偶联激活产生的活性氧 蛋白质。

PROJECT SUMMARY/ABSTRACT Glaucoma is a disease characterized by visual field loss as a result of the death of retinal ganglion cells. Although increased intraocular pressure remains the most clearly defined risk factor for glaucoma, it is becoming clear that a wide range of other factors can also lead to ganglion cell loss. Pharmacological or surgical regulation of intraocular pressure can stabilize many patients but for some there is still a progressive loss of vision. Thus, there is an urgent need to develop new rational strategies to slow or prevent neuronal loss occurring in glaucoma. There is abundant evidence that the eye, like other regions of the CNS, contains endogenous neurotrophic/neuroprotective factors that function to limit cell injury. It is the basic premise of this proposal that these neuroprotective mechanisms can be exploited to prevent much of the cell death associated with diseases such as glaucoma. This proposal focuses on one neuroprotective molecule, CNTF, a factor that has already been shown to have potent neuroprotective effects in a number of CNS regions including the retina and is a leading candidate for slowing the progression of ganglion cell loss. In our preliminary data we present evidence that CNTF supports the survival of purified rat RGCs in low density cultures and that its downstream effector STAT3 prevents RGCs from degenerating in ischemia- reperfusion injury. We now propose a series of experiments to test if RGCs can be prevented from dying in the presence of toxic levels of glutamate by CNTF. In a first aim we will define the pathways used by CNTF to exert its protective action. Second, we will examine whether M¿ller glia can respond to CNTF and provide synergistic protection to RGCs by the secretion of additional neuroprotective factors or a range of other responses. Finally we will test whether the protective pathways activated by CNTF lead to a reduction in reactive oxygen species generation by mitochondria through the activation of mitochondrial uncoupling proteins.