Mechanisms of NMDAR contribution to traumatic injury in retinal ganglion cells

项目摘要 青光眼是全世界最常见的不可逆性失明原因。据估计，它影响了超过3 数百万美国人和10万多人因这种不治之症而失明。通常，最主要的侮辱是 青光眼是眼压升高，导致视神经病变和视网膜轴突受损。 神经节细胞(RGC)。视网膜节细胞是视网膜的输出神经元，将所有视觉信息传递给其他大脑。 区域；他们的死亡导致视觉功能的丧失。目前的治疗选择侧重于解决 眼压升高。虽然这种和类似的干预措施可以延缓青光眼的进展，即使 在最佳治疗下，会出现一些视力障碍，视力丧失是不可逆转的。因此，有一个关键的 需要以神经保护为目的的早期发现和治疗。 动物模型已被证明有助于理解RGC死亡的神经病理学。其中 其中，视神经挤压(ONC)的小鼠模型特别值得注意，因为它导致了精确的时间 视网膜节细胞变性。小鼠和人类一样，有多种形态不同的RGC亚型， 嵌入不同的神经回路，并提供不同的视觉功能。原因还没有确定 经鉴定，许多损伤类型对某些RGC亚型的影响不成比例。了解以下因素 促进细胞存活对于设计改进疾病管理的策略至关重要。 这项建议的目的是分析谷氨酸能NMDA受体在脑血管病变中的作用。 属于不同亚型的单个RGC。NMDA受体是已知的钙超载的介体， 兴奋性毒性，其异常激活可通过多种途径导致细胞死亡。我们将采取一项 结合生物物理模拟、电生理学和谷氨酸的创新方法 和钙成像，提供视网膜神经节细胞结构和功能变化的详细描述 遭受创伤性损伤。我们将集中在生理状态和对刺激的反应上。 受损的神经元。这将使我们能够阐明细胞和细胞代谢状态的差异 与神经元活动相关的参数对视力障碍和预后的贡献。 这项拟议的研究将极大地促进我们对神经元相关机制的理解。 对损害的反应。在研资局人口中学到的教训将结合和整合起来，以制定一种 神经元活动对受侮辱后存活的影响的全面理论描述 泛化以提供对其他神经病理情况的进一步了解。最后，我们的研究将 确定潜在神经保护干预措施的新靶点，以保护视觉功能。

Project Summary Glaucoma is the most prevalent cause of irreversible blindness worldwide. It is estimated that it affects over 3 million Americans and more than 100,000 are blind from this incurable disease. Often, the primary insult in glaucoma is elevated eye pressure, which leads to optic neuropathy and damage to the axons of retinal ganglion cells (RGCs). RGCs are the output neurons of the retina that carry all visual information to other brain regions; their death results in loss of visual function. Current treatment options are focused on addressing elevated intraocular pressure. While this and similar interventions can delay the progression of glaucoma, even with optimal treatment, some visual deficits occur, and vision loss is irreversible. Therefore, there is a critical need for early detection and treatment aimed at neuroprotection. Animal models have proven to be instrumental in understanding the neuropathology of RGC death. Among them, a mouse model of optic nerve crush (ONC) is of particular note because it leads to precisely timed degeneration of RGCs. Mice, like humans, have multiple RGC subtypes that differ in morphology, are embedded in separate neural circuits, and provide distinct visual functions. For reasons that have not yet been identified, many injury types disproportionately affect some RGC subtypes. Understanding the factors that promote cell survival is essential to design strategies to improve disease management. The goal of this proposal is to analyze the role of glutamatergic NMDA receptors to pathological changes in individual RGCs belonging to different subtypes. NMDA receptors are known mediators of calcium overload, excitotoxicity, and their abnormal activation can lead to cell death via multiple pathways. We will take an innovative approach that combines biophysically realistic modeling, electrophysiology, as well as glutamate and calcium imaging to provide a detailed description of the changes in the structure and function of RGCs subjected to traumatic damage. We will focus on the physiological status and responsiveness to stimulation in the injured neuron. This will enable us to elucidate the differences in the metabolic state of the cells and the contribution of parameters associated with the neuronal activity to visual deficits and prognosis. The proposed research will substantially advance our understanding of the mechanisms involved in neuronal responses to damage. The lessons learned in RGC populations will be combined and integrated to develop a comprehensive theoretical description of the impact of neuronal activity on survival after an insult and readily generalized to provide further understanding of other neuropathological conditions. Finally, our research will identify novel targets for potential neuroprotective interventions to preserve visual function.