Molecular Analysis of Retinal Ganglion Cell Death

视网膜神经节细胞死亡的分子分析

• 批准号: 6698520
• 负责人: COLIN J BARNSTABLE
• 金额: $ 36.79万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698520
• 关键词: Muller' s cell; aminoacid metabolism; cell cell interaction; cell death; cysteine endopeptidases; gene expression; genetically modified animals; glaucoma; glutamates; ischemia; laboratory mouse; mitochondria; molecular biology; molecular pathology; neurotoxins; nitric oxide; retinal ganglion; tissue /cell culture

DESCRIPTION (From the Applicant's Abstract): Retinal ganglion cell death is the final common pathway of almost all diseases of the optic nerve including glaucoma. Glaucoma is a leading cause of blindness and, although a number of risk factors have been identified, its causes remain unclear. Excitotoxins may be a major cause of cell death in glaucoma and the overall goal of this project is to determine the molecular mechanisms by which a variety of excitotoxic agents induce ganglion cell apoptosis. The proposal has four specific aims. In the first aim the hypothesis that glutamate induces apoptosis through a caspase-9 mediated pathway will be tested. In addition, other factors, including ischemia will be tested to determine whether they can act synergistically to exacerbate the effects of low concentrations of excitotoxins. In the second specific aim the hypothesis that mitochondrial uncoupling proteins can reduce excitotoxic ganglion cell death will be tested. The sensitivity of ganglion cells to excitotoxic and ischemic insults will be tested in culture and in the intact eye using genetically engineered mouse strains that overexpress or under express the protein UCP2. The third aim will test the hypothesis that functional disorders of Muller glial cells may contribute to excitotoxic ganglion cell death. In particular, a variety of agents will be tested for their ability to inhibit Muller cell glutamate uptake. The final aim will test the hypothesis that direct cell contact can protect ganglion cells from the toxic effects of nitric oxide. The specificity of this effect will be tested with a variety of cell types and the need for membrane contact by living cells will be tested using a variety of biochemical fractions. Overall, the experiments in this proposal will shed light on mechanisms of cell death of particular relevance to glaucoma. They will also further elucidate mechanisms of interaction between retinal ganglion cells and Muller glial cells. By identifying molecules that can alter responses to excitotoxins or ischemia, this proposal is likely to provide potential targets for novel therapeutic interventions to prevent or slow the progression of blindness resulting from glaucoma.

描述（摘自申请人的摘要）：视网膜神经节细胞死亡是 视神经几乎所有疾病的最终公共途径，包括 青光眼。青光眼是失明的主要原因，尽管有许多 已经确定了危险因素，其原因尚不清楚。兴奋毒素可能 成为青光眼中细胞死亡的主要原因和该项目的总体目标 是确定各种兴奋性毒性的分子机制 药物诱导神经节细胞凋亡。该提案具有四个具体目标。在 第一个目的是通过谷氨酸诱导凋亡的假设 caspase-9将测试介导的途径。另外，其他因素， 包括缺血在内，将进行测试以确定它们是否可以采取行动 协同性地加剧低浓度的影响 兴奋毒素。在第二个特定目标中，线粒体的假设 解偶联蛋白可以减少兴奋性神经节细胞死亡。 神经节细胞对兴奋性和缺血性侮辱的敏感性将是 使用基因工程的小鼠在培养和完整的眼中进行测试 过表达或表达蛋白质UCP2的菌株。第三个目标 检验以下假设，即Muller神经胶质细胞的功能障碍可能 有助于兴奋性神经节细胞死亡。特别是多种多样 将测试其抑制Muller细胞谷氨酸的能力 吸收。最终目标将检验直接电池触点的假设 保护神经节细胞免受一氧化氮的毒性作用。特异性 这种效果将通过多种细胞类型进行测试，需要 活细胞的膜接触将使用多种生化测试 分数。总体而言，此提案中的实验将阐明 与青光眼特别相关的细胞死亡机制。他们也会 进一步阐明了视网膜神经节细胞与 Muller神经胶质细胞。通过识别可以改变对响应的分子 兴奋毒素或缺血，该建议可能会提供潜在的目标 为了预防或减缓新的治疗干预措施 青光眼引起的失明。