Molecular Analysis of Retinal Ganglion Cell Death

描述（来自申请人的摘要）：视网膜神经节细胞死亡是视网膜神经节细胞死亡的主要原因。 几乎所有视神经疾病的最终共同途径，包括 青光眼青光眼是导致失明的主要原因，尽管许多 风险因素已经确定，但其原因仍不清楚。兴奋毒素可能 是青光眼细胞死亡的主要原因， 是为了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。该提案有四个具体目标。在 第一个目标是假设谷氨酸通过 将测试半胱天冬酶-9介导的途径。此外，其他因素， 包括局部缺血，将进行测试，以确定他们是否可以发挥作用， 协同地加剧低浓度的 兴奋毒素在第二个具体目标的假设，线粒体 解偶联蛋白可以减少兴奋毒性神经节细胞死亡。 神经节细胞对兴奋性毒性和缺血性损伤的敏感性将是 在培养物和使用基因工程小鼠的完整眼睛中进行测试， 过表达或低表达蛋白UCP 2的菌株。第三个目标将 验证Muller神经胶质细胞功能障碍可能 导致神经节细胞死亡特别是，各种 将测试药物抑制Muller细胞谷氨酸的能力 摄取。最终的目标是检验直接细胞接触可以 保护神经节细胞免受一氧化氮的毒性作用。特异性 将用各种细胞类型测试这种效果， 活细胞的膜接触将使用各种生物化学方法进行测试。 分数总的来说，本提案中的实验将阐明 与青光眼特别相关的细胞死亡机制。他们还将 进一步阐明视网膜神经节细胞之间的相互作用机制， 米勒神经胶质细胞。通过识别可以改变对 兴奋毒素或缺血，这一建议可能提供潜在的目标， 新的治疗干预措施，以防止或减缓进展， 青光眼导致的失明。

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.