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: 8204925
• 负责人: COLIN J BARNSTABLE
• 金额: $ 37.06万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204925
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Affect; Apoptosis; Apoptotic; Biochemical; Biochemical Pathway; Biological Assay; Blindness; Cause of Death; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Ciliary Neurotrophic Factor; Data; Disease; Disease Progression; Environment; Eye; Functional disorder; Generations; Glaucoma; Glutamates; Goals; Homeostasis; Hypoxia; Individual; Injury; Lead; Membrane Potentials; Mitochondria; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular Analysis; Muller' s cell; N-Methylaspartate; Neuroglia; Operative Surgical Procedures; Optic Nerve; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiology; Play; Production; Proto-Oncogene Proteins c-akt; Rattus; Reactive Oxygen Species; Regulation; Reperfusion Injury; Research; Resistance; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Signaling Molecule; System; Testing; Therapeutic Agents; Visual Fields; cell injury; cytokine; density; design; excitotoxicity; ganglion cell; knockout animal; mitochondrial uncoupling protein; neuron loss; neurotrophic factor; novel; novel therapeutics; polypeptide; prevent; research study; response; 1-Phosphatidylinositol 3-Kinase; Acute; Affect; Apoptosis; Apoptotic; Biochemical; Biochemical Pathway; Biological Assay; Blindness; Cause of Death; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Ciliary Neurotrophic Factor; Data; Disease; Disease Progression; Environment; Eye; Functional disorder; Generations; Glaucoma; Glutamates; Goals; Homeostasis; Hypoxia; Individual; Injury; Lead; Membrane Potentials; Mitochondria; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular Analysis; Muller' s cell; N-Methylaspartate; Neuroglia; Operative Surgical Procedures; Optic Nerve; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiology; Play; Production; Proto-Oncogene Proteins c-akt; Rattus; Reactive Oxygen Species; Regulation; Reperfusion Injury; Research; Resistance; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Risk Factors; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Signaling Molecule; System; Testing; Therapeutic Agents; Visual Fields; cell injury; cytokine; density; design; excitotoxicity; ganglion cell; knockout animal; mitochondrial uncoupling protein; neuron loss; neurotrophic factor; novel; novel therapeutics; polypeptide; prevent; research study; response

PROJECT SUMMARY/ABSTRACT Glaucoma is a disease characterized by visual field loss as a result of the death of retinal ganglion cells. Although increased intraocular pressure remains the most clearly defined risk factor for glaucoma, it is becoming clear that a wide range of other factors can also lead to ganglion cell loss. Pharmacological or surgical regulation of intraocular pressure can stabilize many patients but for some there is still a progressive loss of vision. Thus, there is an urgent need to develop new rational strategies to slow or prevent neuronal loss occurring in glaucoma. There is abundant evidence that the eye, like other regions of the CNS, contains endogenous neurotrophic/neuroprotective factors that function to limit cell injury. It is the basic premise of this proposal that these neuroprotective mechanisms can be exploited to prevent much of the cell death associated with diseases such as glaucoma. This proposal focuses on one neuroprotective molecule, CNTF, a factor that has already been shown to have potent neuroprotective effects in a number of CNS regions including the retina and is a leading candidate for slowing the progression of ganglion cell loss. In our preliminary data we present evidence that CNTF supports the survival of purified rat RGCs in low density cultures and that its downstream effector STAT3 prevents RGCs from degenerating in ischemia- reperfusion injury. We now propose a series of experiments to test if RGCs can be prevented from dying in the presence of toxic levels of glutamate by CNTF. In a first aim we will define the pathways used by CNTF to exert its protective action. Second, we will examine whether M¿ller glia can respond to CNTF and provide synergistic protection to RGCs by the secretion of additional neuroprotective factors or a range of other responses. Finally we will test whether the protective pathways activated by CNTF lead to a reduction in reactive oxygen species generation by mitochondria through the activation of mitochondrial uncoupling proteins.

项目摘要/摘要 青光眼是一种因视网膜神经节死亡而导致视野丧失的疾病 细胞。尽管升高的眼内压仍然是青光眼最明确定义的风险因素，但它是 很明显，其他各种因素也会导致神经节细胞损失。药理或 眼内压的手术调节可以稳定许多患者，但对于某些患者，仍有一个进行性 视力丧失。这是迫切需要制定新的理性策略来减缓或防止神经元损失 发生在青光眼中。 有大量证据表明，眼睛与中枢神经系统的其他区域一样 神经营养/神经保护因子，可限制细胞损伤。这是本提案的基本前提 可以探索这些神经保护机制，以防止与 诸如青光眼等疾病。该提案的重点是一个神经保护分子CNTF，一个具有 已经显示在包括视网膜在内的许多CNS区域中具有潜在的神经保护作用 并且是减慢神经节细胞损失进展的领先候选人。 在我们的初步数据中，我们提供了证据，表明CNTF支持纯化的大鼠RGC在 低密度培养物，其下游效应子STAT3可防止RGC在缺血 - 再灌注损伤。现在，我们提出了一系列实验，以测试是否可以防止RGC在 CNTF的谷氨酸有毒水平的存在。在第一个目标中，我们将定义CNTF使用的途径 采取保护性行动。其次，我们将检查M ller Glia是否可以对CNTF做出反应并提供 通过分泌其他神经保护因素或其他其他 回答。最后，我们将测试CNTF激活的受保护途径是否导致减少 线粒体通过线粒体解偶联而产生活性氧 蛋白质。