眼压感受性三叉神经末梢蕴含青光眼药物治疗新靶点TRPA1

Glaucoma is one of the most common causes of blindness, and increased intraocular pressure (IOP) is its main risk factor. Central nervous system regulates IOP through a neural feedback mechanism, and trigeminal nerve has been found to be the afferent pathway. Our previous study on baroreceptor of IOP (supported by a grant from the National Natural Science Foundation of China No. 81070727) has found that trigeminal nerve endings in inner walls of rat anterior chambers are mechanosensitive, and TRAP1 is the main mechanosesitive channel in the membrane. We also have found TRPA1 is the common target of bimatoprost and cannabinoid, both of which can activate TRAP1 to sensitize mechanosensitive trigeminal nerve endings. Therefore, we hypothesize that mechanosensitive trigeminal nerve endings form baroreceptors of IOP, and activation of TRPA1 may decrease IOP by sensitizing baroreceptors of IOP. We are going to investigate influence of TRPA1 knockout：①on mechanosensitivity of trigeminal nerve endings, ②on IOP, on retinal ganglion cells, on optic disk, ③on visual function, and hypotensive effect of bimatoprost and cannabinoid using TRPA1 knockout rats. We expect that our research may find out mechanism of IOP baroreceptor, and new targets of glaucoma management.

青光眼是常见致盲眼病，眼压升高是主要危险因素。中枢神经系统通过神经反馈机制参与眼压自稳调节，三叉神经是传入途径。我们前期针对眼压感受器的研究（国家自然基金项目，编号：81070727）发现：大鼠眼前房内壁结构中的三叉神经末梢具有机械敏感性，TRPA1是重要的机电转换分子；TRPA1是降眼压药物贝美前列腺素和大麻素共同的作用靶点，二药均能激活TRPA1增敏机械敏感性三叉神经末梢。我们假设：机械敏感性三叉神经末梢构成眼压感受器，机电转换分子TRPA1的激活能增敏眼压感受器降低眼压，TRPA1是青光眼药物治疗的新靶点。本项目将以TRPA1基因敲除鼠为研究对象，从在体及离体水平系统研究TRPA1缺失：①对三叉神经末梢机械敏感性的影响；②对眼压、视网膜节细胞、视神经乳头及视功能的影响；③对贝美前列腺素及大麻素降眼压效应的影响。本研究有望揭示眼压感受器的工作机制，发现新的青光眼治疗靶点。

中枢神经系统通过神经反馈机制参与眼压自稳调节，我们之前的研究发现：分布在大鼠眼前房内壁结构中的三叉神经末梢具有机械敏感性，TRPA1是重要的机电转换分子。本项目假说：机械敏感性三叉神经末梢构成眼压感受器，其胞膜上蕴含机电转换分子TRPA1通道，TRPA1的激活能增敏眼压感受性三叉神经末梢发挥降眼压作用。本项目以TRPA1基因敲除鼠为研究对象，发现TRPA1基因敲除鼠出现角膜及眼球增大、眼压升高、视网膜神经节细胞数目减少等先天性青光眼的体征，为TRPA1参与眼压调控及青光眼发病提供了有力的活体研究证据。我们还依托TRPA1基因敲除鼠进一步研究天然药物TRPA1激动剂的降眼压效应，研究进行中。在本项目研究过程中我们还应用神经示踪技术标记出以前房三叉神经末梢为起点的眼压神经性调节环路，同时还应用MCMV前房注射构建了青睫综合征动物模型。本研究结果为眼压的神经性调节机制提供了证据，为发现新的青光眼药物靶点指出方向。