Molecular Mechanisms of Sigma Receptor 1-Mediated Neuroprotection

描述（由申请人提供）：本提案的一般目的是为主要研究者（PI）提供成为成功和独立的视力研究者所需的经验和技能。我的长期目标是发展一个独立的研究项目，旨在发现青光眼的治疗方法。青光眼是一种年龄相关性视神经病变，其导致视神经内的视网膜神经节细胞（RGC）死亡。在本申请中，我们提出测试一种新的目标，分子伴侣蛋白σ受体1（CR 1）的配体，是否可以保护RGCs从死亡条件下的昏迷压力。青光眼的几种模型涉及肿瘤坏死因子（TNF 1）作为引起青光眼中RGC死亡的应激源。我们将使用体外和体内模型系统来测试CR 1通过抑制视网膜神经胶质细胞释放TNF 1和通过改变RGCs对TNF 1的信号应答来保护RGCs的假设。我们将使用最近发现的诱导眼内压升高的啮齿动物模型和基因敲除小鼠技术来验证我们的假设，主要有以下三个目的：1）使用体外模型系统来验证CR 1配体调节胶质细胞炎症反应的假设。2)检验CR 1激活将TNF 1介导的信号传导的平衡向RGC内的存活转移的假设。3)在青光眼的体内模型中，检验CR 1活化改变胶质细胞和神经元对高眼压的反应以及CR 1配体将抑制胶质细胞活化并防止RGC死亡的假设。 公共卫生相关性：青光眼是全球第二大致盲原因。由于人口老龄化，到2020年将有大约8 000万人患有这种疾病。青光眼的一个主要危险因素是眼内压（IOP）升高，这是目前唯一可改变的危险因素。然而，降低IOP的治疗可能导致威胁视力的并发症。此外，研究表明，在接受标准降眼压治疗的患者中，多达50%的患者视神经变性继续进展。因此，需要新的神经保护靶点来预防青光眼性视力丧失。该提案测试了青光眼治疗的新靶点！

DESCRIPTION (provided by applicant): 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(CR1), can protect RGCs from death under conditions of glaucomatous stress. Several models of glaucoma have implicated tumor necrosis factor (TNF1) as a stressor that causes RGC death in glaucoma. We will use in vitro and in vivo model systems to test the hypothesis that CR1 protects RGCs by suppressing retinal glial cell release of TNF1 and by altering the signaling response of RGCs to TNF1. 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 CR1 ligands modulate glial inflammatory responses using in vitro model systems. 2) Test the hypothesis that CR1 activation shifts the balance of TNF1 mediated signaling towards survival within RGCs. 3) Test the hypothesis that CR1 activation alters glial and neuronal responses to ocular hypertension and that CR1 ligand will suppress glial activation and protect against RGC death in an in vivo model of glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is the second leading cause of blindness worldwide. Because of the aging population, approximately 80 million people will be afflicted with this disease by the year 2020. A major risk factor for glaucoma is increased intraocular pressure (IOP), and this is currently the only modifiable risk factor. However, treatments that lower IOP can cause vision-threatening complications. In addition, studies indicate that progression of optic nerve degeneration continues in as many as 50% of patients treated with standard IOP-lowering therapy. Therefore, new neuroprotective targets for preventing glaucomatous vision loss are needed. This proposal tests a novel target for glaucoma treatment!