Mechanisms underlying endothelin mediated neurodegeneration in glaucoma

项目总结： 内皮素B(ETB)受体已被证明在多种眼组织中升高。 青光眼的动物模型。我们的初步数据显示ETA受体也增加 在高眼压大鼠的视网膜中。我们实验室之前的工作表明，许多 高眼压的不良影响包括视神经轴索损伤和视网膜神经节 ETB受体缺陷大鼠的细胞(RGC)损失减轻。这表明了一种因果关系 ETB受体与神经退行性变然而，内皮素介导的机制 视神经和视网膜节细胞的神经退行性变尚不清楚。主要假设 内皮素受体的拮抗作用通过减弱 C-jun氨基末端激酶(JNK)和p38蛋白在眼球运动中的作用 高血压。目前的赠款申请将包括以下具体目标：1) 确定内皮素受体是否通过以下途径介导视网膜节细胞及其轴突的神经变性 激活啮齿动物c-jun氨基末端激酶(JNK)和p38-MAP激酶信号通路。2) 阐明内皮素诱导培养的细胞凋亡的信号机制 原代视网膜神经节细胞。3)研究内皮素受体拮抗剂是否具有神经保护作用 在高眼压的啮齿动物模型中。这个项目的亮点包括基因疗法。 用腺相关病毒敲除ETA和ETB受体干预 测定其对高眼压大鼠的神经保护作用。另一种方法 拨款中建议使用内皮素受体拮抗剂来阻断内皮素受体。 促进高眼压大鼠的神经保护作用。该项目将评估以下方面的贡献 内皮素受体在神经退行性变中的作用及勾画JNK和p38的MAP 高眼压时内皮素受体介导的神经退行性变中的激酶通路 在老鼠身上。该项目还将产生分子和药理学方面的可能性 阻断内皮素受体从而促进视网膜节细胞及其神经保护的干预 轴突。从这些研究中获得的基本信息将有助于 治疗青光眼的神经保护剂。

Project Summary: Endothelin B (ETB) receptors have been shown to be elevated in various ocular tissues in animal models of glaucoma. Our preliminary data suggest that ETA receptors are also increased in retinas of rats with elevated IOP. Previous work from our laboratory showed that many of the deleterious effects of ocular hypertension including optic nerve axonal injury and retinal ganglion cell (RGC) loss are attenuated in ETB receptor-deficient rats. This suggests a causative role of ETB receptors in neurodegeneration. However, the mechanisms underlying endothelin mediated neurodegeneration of the optic nerve and RGCs are not understood. The main hypothesis that antagonism of the endothelin receptors promotes neuroprotection by attenuating the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathway during ocular hypertension. The current grant application will comprise of the following specific aims: 1) Determine if the endothelin receptors mediate neurodegeneration of RGCs and their axons by activating c-Jun N-terminal kinase (JNK) and p38 MAP kinase signaling pathways in rodents. 2) Elucidate the signaling mechanisms involved in endothelin mediated apoptosis of cultured primary retinal ganglion cells. 3) Investigate if endothelin receptor antagonism is neuroprotective in a rodent model of ocular hypertension. The highlights of this project include a gene therapy intervention using adeno-associated viral knock down of ETA as well as the ETB receptor to determine its neuroprotective effects during ocular hypertension in rats. Another approach proposed in the grant is the use of endothelin receptor antagonists to block endothelin receptors and promote neuroprotection in IOP elevated rats. The project will assess the contribution of endothelin receptors to neurodegeneration and delineate the role of the JNK and p38 MAP kinase pathway in endothelin receptor-mediated neurodegeneration during ocular hypertension in rats. The project will also generate possibilities for molecular as well as pharmacological interventions to block endothelin receptors thereby promote neuroprotection of RGCs and their axons. The basic information gained from these studies would facilitate development of neuroprotective agents for treatment of glaucoma.