在國家 “973”、國家自然科學基金和上海市基礎(chǔ)研究重點課題資助下,，復旦大學腦科學研究院,、復旦大學附屬眼耳鼻喉科醫(yī)院王中峰教授、孫興懷教授,、楊雄里院士率領(lǐng)的視網(wǎng)膜研究團隊發(fā)現(xiàn)青光眼視網(wǎng)膜膠質(zhì)細胞激活新機制,，為臨床上防止青光眼惡化,，以及有效阻止青光眼所導致的視網(wǎng)膜神經(jīng)細胞的死亡（失明）提供了新的理論依據(jù),。該成果已刊登在最新一期的國際神經(jīng)科學著名期刊《神經(jīng)科學雜志》上。
青光眼是由于視網(wǎng)膜神經(jīng)節(jié)細胞損傷,、不可逆性視功能損害疾病,，已成為世界上第二大致盲性眼病，其臨床癥狀主要是“高眼壓”引起的眼睛不同程度的疼痛,。研究發(fā)現(xiàn)青光眼所導致的失明,，與視網(wǎng)膜膠質(zhì)細胞被激活密切相關(guān)，幾乎所有患有神經(jīng)系統(tǒng)（包括視網(wǎng)膜）損傷疾病的患者都伴隨有膠質(zhì)細胞“被激活”現(xiàn)象,，該激活機制在青光眼神經(jīng)節(jié)細胞損傷中究竟如何扮演 “破壞性角色”,，如何使膠質(zhì)細胞“不被激活”,，一直是各國科學家探討和研究的重大課題。
為破解這一重大課題,，王中峰教授,、孫興懷教授、楊雄里院士率領(lǐng)博士研究生季敏,、苗艷穎等,，利用老鼠建立“高眼壓模型”來模擬人的青光眼疾病，研究后發(fā)現(xiàn),，“高眼壓”導致視網(wǎng)膜內(nèi)一種叫“穆勒”的主要膠質(zhì)細胞被激活了,。后來，他們又通過在眼睛的玻璃體內(nèi)注射特異性的藥物的方法,，結(jié)果發(fā)現(xiàn)青光眼會導致視網(wǎng)膜內(nèi)一種作為細胞之間“光信號傳遞”的氨基酸使谷氨酸的量增多,，增多的谷氨酸會與膠質(zhì)細胞膜上的一種稱為“受體”的蛋白質(zhì)結(jié)合，然后通過細胞內(nèi)一系列的反應,，結(jié)果使膠質(zhì)細胞膜上的一種能夠通透鉀離子的蛋白質(zhì)的量變少了,，正是這種蛋白質(zhì)量的減少，最后導致膠質(zhì)細胞被激活,。而激活的膠質(zhì)細胞會釋放出許多有害物質(zhì),，引起視網(wǎng)膜的神經(jīng)細胞大量死亡，最終導致失明,。（生物谷Bioon.com）
doi:10.1523/JNEUROSCI.1291-12.2012
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Group I mGluR-Mediated Inhibition of Kir Channels Contributes to Retinal Müller Cell Gliosis in a Rat Chronic Ocular Hypertension Model
Min Ji, Yanying Miao, Ling-Dan Dong, Jie Chen, Xiao-Fen Mo, Shi-Xiang Jiang, Xing-Huai Sun, Xiong-Li Yang, and Zhongfeng Wang
Müller cell gliosis, which is characterized by upregulated expression of glial fibrillary acidic protein (GFAP), is a universal response in many retinal pathological conditions. Whether down-regulation of inward rectifying K(+) (Kir) channels, which commonly accompanies the enhanced GFAP expression, could contribute to Müller cell gliosis is poorly understood. We investigated changes of Kir currents, GFAP and Kir4.1 protein expression in Müller cells in a rat chronic ocular hypertension (COH) model, and explored the mechanisms underlying Müller cell gliosis. We show that Kir currents and Kir4.1 protein expression in Müller cells were reduced significantly, while GFAP expression was increased in COH rats, and these changes were eliminated by MPEP, a group I metabotropic glutamate receptors (mGluR I) subtype mGluR5 antagonist. In normal isolated Müller cells, the mGluR I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) suppressed the Kir currents and the suppression was blocked by MPEP. The DHPG effect was mediated by the intracellular Ca(2+)-dependent PLC/IP(3)-ryanodine/PKC signaling pathway, but the cAMP-PKA pathway was not involved. Moreover, intravitreal injection of DHPG in normal rats induced changes in Müller cells, similar to those observed in COH rats. The DHPG-induced increase of GFAP expression in Müller cells was obstructed by Ba(2+), suggesting the involvement of Kir channels. We conclude that overactivation of mGluR5 by excessive extracellular glutamate in COH rats could contribute to Müller cell gliosis by suppressing Kir channels.
