Retinal Ganglion Cell Plasticity in Glaucoma

描述（由申请人提供）：视网膜神经节细胞（RGC）死亡是开角型青光眼（OAG）和大多数视神经病变不可逆性失明的主要原因。该项目的目标是通过获得了解RGC脆弱性病因所需的信息来预防这些疾病中的失明，并利用这种理解来开发预防细胞死亡的方法。我们的目的是确定RGC对应激源的敏感性，如眼压升高，代谢负荷，和神经营养因子（NT）缺乏症的青光眼和视神经病变的小鼠模型在进行性RGC功能障碍死亡前的阶段（关键期）。我们的中心假设是，RGC死亡是自动调节/适应过程失败的结果，不能再维持正常的RGC稳态，导致RGC电反应性丧失。在关键时期，RGC的反应性是可变的（可塑性）的压力源，如IOP，代谢需求和NT的支持，从而提供了一个理论基础和治疗干预的目标。使用创新的方法，我们将急性调节这些应激源的水平，并同时评估随着时间的推移，使用图形视网膜电图（PERG）和视觉诱发电位（VEP）的RGC电反应的可修改性。我们还将使用最先进的光学相干断层扫描（OCT）来连续监测视网膜内层的厚度，以及终点时的视网膜免疫组织化学。我们将通过完成以下目标来达到我们的目标和目的：1）在青光眼和视神经病变的小鼠模型中检验RGC可塑性发生在特定时间窗内的假设。模型将是青光眼的Myoc转基因小鼠、多发性硬化的ND 4转基因小鼠和视神经炎的MOG特异性TCR转基因小鼠。对照组为相应的非病理性同源小鼠。我们将通过改变身体姿势非侵入性地改变IOP，或者通过闪烁光非侵入性地改变代谢需求，并且将测量在OCT信号损失之前PERG/VEP信号的相应变化; 2）测试RGC可塑性在慢性NT缺乏的小鼠模型中是可诱导的假设。我们将在C57 BL/6 J和DBA/2 J小鼠中进行上级丘（SC）的单侧损伤，并将量化每只眼睛中PERG和OCT信号的变化。我们还将在SC损伤的小鼠中诱导IOP和代谢应激，以量化PERG信号的获得性易感性。我们的研究成功完成将建立RGC易感性的新概念模型，并将提高我们检测疾病发作、监测其进展和治疗效果的技术能力，最终改变临床实践。这将代表该领域的一个重大进展，并将对青光眼和其他涉及RGC的神经退行性疾病的未来研究产生影响。

DESCRIPTION (provided by applicant): Retinal ganglion cell (RGC) death is the primary cause of irreversible blindness in Open Angle Glaucoma (OAG) and most optic neuropathies. The goal of this project is to prevent blindness in these diseases by obtaining the information needed to understand the etiology of RGC vulnerability, and use this understanding to develop approaches that prevent cell death. Our objective is determining RGC susceptibility to stressors such as IOP elevation, metabolic load, and neurotrophic factor (NT) deficiency in mouse models of glaucoma and optic neuropathy during the stage of progressive RGC dysfunction preceding death (critical period). Our central hypothesis is that RGC death is the result of failure of autoregulatory/adaptive processes that can no longer sustain normal RGC homeostasis, resulting in loss of RGC electrical responsiveness. During the critical period, RGC responsiveness is modifiable (plastic) upon stressors such as IOP, metabolic demand and NT support, thus providing a rationale and a target for therapeutic intervention. Using innovative methods, we will acutely modulate the levels of these stressors and simultaneously assess modifiability of RGC electrical responsiveness over time using pattern electroretinogram (PERG) and visual evoked potential (VEP). We will also use state-of-the-art optical coherence tomography (OCT) to serially monitor thickness of inner retinal layers, as well as retinal immunohistochemistry at endpoint. We will attain our goal and objective by accomplishing the following aims: 1) Test the hypothesis that RGC plasticity occurs in a specific time window in mouse models of glaucoma and optic neuropathy. Models will be the Myoc transgenic mouse of glaucoma, the ND4 transgenic mouse of multiple sclerosis, and the MOG-specific TCR transgenic mouse of optic neuritis. Controls will be corresponding non-pathological congenic mice. We will non-invasively alter either IOP with changes of body posture, or the metabolic demand with flickering light, and will measure corresponding changes of the PERG/VEP signal that precede loss of OCT signal; 2) Test the hypothesis that RGC plasticity is inducible in mouse models of chronic NT deficiency. We will perform unilateral lesions of the superior colliculus (SC) in C57BL/6J and DBA/2J mice and will quantify changes of the PERG and OCT signal in each eye. We will also induce IOP and metabolic stress in SC-lesioned mice to quantify acquired susceptibility of the PERG signal. Successful completion of our research will establish a new conceptual model of RGC susceptibility, and will improve our technical capability of detecting diseases' onset, monitoring their progression and the effect of treatment, eventually changing clinical practice. This will represent a significant advancement in the field and will be influential on future research on glaucoma and other neurodegenerative diseases involving RGC.