The Role of Pannexin1 in Ischemic Injury of Retinal Ganglion Cells

摘要 我们的长期目标是防止视网膜缺血引起的神经元丢失和功能缺陷。 根据我们的目标，我们已经确定了一种新的，几乎没有被探索的膜通道 蛋白PAnnexin1(Panx1)，作为发现新疗法的有希望的来源。我们 证实Panx1作为缺血性神经元损伤的分子介质发挥作用，以及 基因消融该通道可保护视网膜神经节细胞免受缺血损伤。我们的 中心假说指出，Panx1是外部网络的关键“汇聚中心” 压力源。我们建议的研究将比较不同毒性的相对贡献。 Panx1介导的机制并识别哪些刺激或它们的组合触发 缺血时视网膜神经节细胞内此通道的病理性开放。 具体目的是：1)分析由Panx1通道触发的毒性通路 开放其对RGC损伤的相对贡献毒性~2)比较 部分抑制与完全阻断或消融在体视网膜Panx1通道的比较 缺血再灌注模型。我们将同时关注神经元的存活和视网膜的保存 脑缺血后的功能。 意义重大。保护视网膜神经元免受缺血损伤是全面 治疗策略。Panx1介导的毒性途径及其作用机制的研究进展 对神经元损伤的贡献将永久性地改变概念和治疗方法 视网膜和脑缺血的治疗方法。我们将利用开发的专业知识和独特的 为这项提议设计的工具，用于评估Panx1封锁的可行性，以抑制或 预防短暂性脑缺血中的视力丧失是一个重要的临床问题和NIH NEI 研究目的。

Abstract Our long-term goal is to prevent neuronal loss and functional deficits in retinal ischemia. Pursuant to our objective, we have identified a new, scantily explored membrane channel protein pannexin1 (Panx1), as a promising source for discovering new therapies. We established that Panx1 function as a molecular mediator of ischemic neuronal injury, and genetic ablation of this channel protects retinal ganglion cells from ischemic damage. Our central hypothesis states that Panx1 serves as a critical "convergence hub" for external stressors. Our proposed studies will compare relative contribution of distinct toxicity mechanisms mediated by Panx1 and identify which stimuli or their combinations trigger pathological opening of this channel in vulnerable retinal ganglion cells in ischemia. Specific Aims are designed to: 1) analyze toxicity pathways triggered by the Panx1 channel opening for their relative contribution toxicity to RGC injury~ 2) Compare protective effects of partial inhibition vs. full blockade or ablation of Panx1 channel in vivo in experimental retinal ischemia-reperfusion model. We will focus on both neuronal survival and preservation of retinal functionality following ischemia. Significance. Protecting retinal neurons from ischemic injury is essential for a comprehensive therapeutic strategy. The understanding of the Panx1-mediated toxicity pathways and their contribution to neuronal injury will permanently alter both conceptual and therapeutic approaches to retinal and brain ischemia. We will use the expertise developed and the unique tools designed for this proposal to evaluate the feasibility of Panx1 blockade for suppressing or preventing the vision loss in transient ischemia, an important clinical problem and the NIH NEI research objective.