Molecular Mechanisms of Sigma Receptor 1-Mediated Neuroprotection

项目总结： 这项建议的一般目的是向首席调查员(PI)提供 成为成功的独立愿景所必需的经验和技能 研究员。我的长期目标是开发一个独立的研究项目 寻找治疗青光眼的方法。青光眼是一种与年龄相关的视神经疾病。 导致视神经内视网膜神经节细胞死亡的神经病 很有胆量。在这个应用中，我们建议测试一个新的靶标的配体是否 分子伴侣蛋白Sigma受体1(？R1)可保护视网膜节细胞免于死亡 在青光眼应激状态下。几种青光眼模型与此有关 肿瘤坏死因子是导致青光眼视网膜色素上皮细胞死亡的应激源。我们会 使用体外和体内模型系统来检验假设，即？R1通过 抑制视网膜神经胶质细胞释放肿瘤坏死因子及改变其信号反应 RGCs转化为肿瘤坏死因子。我们将使用最近发现的啮齿动物模型来诱导 眼压和基因敲除老鼠技术来验证我们的假设。 将实现以下三个目标： 1)验证假设，即R1配体使用in调节神经胶质炎症反应 体外模型系统。 2)验证假设，即R1的激活改变了肿瘤坏死因子介导的信号平衡 为了在RGC中生存。 3)验证R1激活改变神经胶质细胞和神经元对眼睛反应的假设 高血压和R1配体将抑制胶质细胞激活并保护RGC 青光眼活体模型中的死亡。

Project Summary: The general purpose of this proposal is to provide the principle investigator (PI) with the experience and skills necessary to become a successful and independent vision researcher. My long-term goal is to develop an independent research program directed toward discovery of treatments for glaucoma. Glaucoma is an age-related optic neuropathy that results in the death of retinal ganglion cells (RGCs) within the optic nerve. In this application, we propose to test whether ligands for a novel target, the molecular chaperone protein sigma receptor 1(¿R1), can protect RGCs from death under conditions of glaucomatous stress. Several models of glaucoma have implicated tumor necrosis factor (TNF¿) as a stressor that causes RGC death in glaucoma. We will use in vitro and in vivo model systems to test the hypothesis that ¿R1 protects RGCs by suppressing retinal glial cell release of TNF¿ and by altering the signaling response of RGCs to TNF¿. We will use a recently discovered rodent model for inducing increased intraocular pressure and knockout mouse technology to test our hypothesis.The following three aims will be addressed: 1) Test the hypothesis that ¿R1 ligands modulate glial inflammatory responses using in vitro model systems. 2) Test the hypothesis that ¿R1 activation shifts the balance of TNF¿ mediated signaling towards survival within RGCs. 3) Test the hypothesis that ¿R1 activation alters glial and neuronal responses to ocular hypertension and that ¿R1 ligand will suppress glial activation and protect against RGC death in an in vivo model of glaucoma.