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中的神经元损失和功能缺陷。 根据我们的目标，我们已经确定了一个新的，很少探索膜通道 蛋白质pannexin 1（Panx 1），作为发现新疗法的有前途的来源。我们 建立了Panx 1作为缺血性神经元损伤分子介质的功能， 该通道的遗传消融保护视网膜神经节细胞免受缺血性损伤。我们 中心假设指出，Panx 1作为一个关键的“收敛枢纽”，为外部 压力源我们提出的研究将比较不同毒性的相对贡献 Panx 1介导的机制，并确定哪些刺激或其组合触发 缺血时脆弱的视网膜神经节细胞中该通道的病理性开放。 具体目的旨在：1）分析Panx 1通道触发的毒性途径 开放的相对贡献毒性RGC损伤~ 2）比较保护作用的 实验性视网膜病变中体内Panx 1通道的部分抑制与完全阻断或消融 缺血再灌注模型。我们将重点关注神经元的存活和视网膜的保护。 缺血后的功能。 意义保护视网膜神经元免受缺血性损伤对于全面的 治疗策略对Panx 1介导的毒性途径及其作用机制的认识 对神经元损伤的贡献将永久地改变概念和治疗 视网膜和脑缺血的方法。我们将利用开发的专业知识和独特的 为该提案设计的工具，用于评估Panx 1阻断抑制或 预防短暂性缺血中的视力丧失，这是一个重要的临床问题， 研究目标。

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.