受体酪氨酸激酶ephrinB/EphB信号在慢性高眼压大鼠视网膜神经节细胞损伤中的作用及其机制研究

受体酪氨酸激酶ephrin/Eph信号在神经系统的发育、突触可塑性、神经再生和修复等过程中有重要作用。近年的研究发现，在视网膜疾病（如青光眼）的病理过程中，伴随有该信号系统在视神经轴突上的表达上调，但其在神经节细胞损伤中的作用和机制还是尚待研究的重要问题。我们在慢性高眼压动物模型上的初步实验结果提示，该信号系统的激活可能通过调控谷氨酸受体导致神经节细胞的损伤。为此，本课题以慢性高眼压为模型，利用免疫组化、Western blot、电生理、钙成像和玻璃体显微注射等多学科研究手段，在视网膜切片、培养的神经节细胞等上，研究激活ephrinB/EphB信号对视网膜神经节细胞谷氨酸受体(NMDA受体NR1亚单位、AMPA受体GluR2亚单位和代谢型受体mGluR I)的调控及其机制，分析其在神经节细胞凋亡中的作用，从而为阐明青光眼视网膜神经节细胞损伤的机制以及有效地防治青光眼提供理论参考依据。

Receptor tyrosine kinase ephrin/Eph signaling plays important roles in neuronal development, synaptic plasticity, neuronal repair and regeneration etc. Recent studies showed that ephrinB/EphB signaling was up-regulated in axon of retinal ganglion cells in experimental glaucoma models. However, the effects and mechanisms of ephrinB/EphB in ganglion cell injury is largely unknown. Our preliminary results obtained from a rat chronic ocular hypertension model showed that activation of ephrinB/EphB reverse signaling may modulate glutamate receptors, thus resulting in the retinal ganglion cell apoptosis. In the present proposal, by using immunohistochemistry, Western blot, patch-clamp recordings, calcium images and intravitreal microinjection techniques, we aim to explore the changes in ephrinB/EphB protein expression in the retinal cells in a rat chronic ocular hypertension (COH) model, and to investigate the modulatory effects of ephrineB/EphB signaling on glutamate receptors, including NR1 subunit of NMDA receptors,GluR2 subunit of AMPA receptors and mGluR I, and the mechanisms underlying ephrineB/EphB signaling-induced apoptosis of retinal ganglion cells. The experiments will be done in retinal slices, retinal ganglion cell cultures. Our prospective research achievements would provide a scientific basis for illuminating the mechanisms of retinal ganglion cell injury and for effctively preventing and curing glaucoma.