双孔钾离子通道TASK-3对视网膜神经节细胞兴奋性调节作用及激动TASK-3保护视网膜缺血损伤机制的研究

视网膜缺血主要使视网膜神经节细胞（RGC）损伤，从而导致严重的视力损害，甚至失明。缺血使RGC过度兴奋，启动其凋亡程序。除解除梗阻恢复血供外，目前尚缺少抑制RGC过度兴奋以保护RGC的方法。双孔钾离子通道是一类提供背景钾电流的通道，可调控神经元兴奋性，但其在视网膜中的功能则尚不清楚。申请人前期研究发现酸敏感性双孔钾离子通道3（TASK-3）在RGC中高表达，并功能性地参与其动作电位的生成，调控其兴奋性。激动TASK-3可以降低RGC兴奋性，是视网膜缺血治疗的潜在方法。本课题拟运用电生理膜片钳、特异性药理学工具、基因敲除小鼠、动物行为学、小鼠视网膜缺血模型等技术深入探究：1）在生理状态下，TASK-3参与调控视觉敏感性的机制；2）RGC中TASK-3参与视网膜缺血发生发展的机制；3）过表达TASK-3和激动TASK-3对视网膜缺血中RGC损伤的保护作用；为发现视网膜缺血治疗新方法提供依据。

Retinal ischemia causes retinal ganglion cells (RGCs) injuries which leads to heavily vision loose or blind and the decline of patients’ quality of life. Retinal ischemia makes RGCs over-excited which starts apoptosis. Besides removing the infarction, rare methods were found to dampen RGCs excitability and protect RGCs. The two-pore-domain potassium channels (K2P) provide background potassium currents to regulate neuron excitability. The functions of K2P are rarely known in retina. Our preliminary data showed that TASK-3, an acid-sensitive K2P, was highly expressed in RGCs, functionally involved in the action potential generation, and regulated cell excitability. Activating TASK-3 dampens the excitability of RGCs which is a potential way for retinal ischemia RGCs protection. We plan to use electrophysiological tools, specific pharmacological tools, TASK-3 KO mice, animal behavior tests, and mouse retinal ischemia model to explore: 1) the function of TASK-3 in regulating visual sensitivity under physiological condition; 2) the roles of TASK-3 participating in retinal ischemia; and 3) the contributions of overexpression of TASK-3 and activation of TASK-3 to retinal ischemia protection which would reveal new ways for retinal ischemia treatment.