Molecular Analysis of Retinal Ganglion Cell Death

视网膜神经节细胞死亡的分子分析

基本信息

批准号：
8008786
负责人：
COLIN J BARNSTABLE
金额：
$ 37.07万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8008786
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&apos 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 public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): 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 Muller 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. PUBLIC HEALTH RELEVANCE: Glaucoma is a blinding disease that affects over 65 million people worldwide. There is still not a good understanding of the basic biochemical mechanisms which cause the death of retinal cells and subsequent loss of vision. This research will identify some of these biochemical pathways. The results of this research will lead to the identification of target molecules for which new therapeutic drugs can be designed.

描述（由申请人提供）：青光眼是视网膜神经节细胞死亡的视野丧失的一种疾病。尽管人眼压增加仍然是青光眼最明确定义的危险因素，但越来越明显的是，许多其他因素也会导致神经节细胞损失。眼内压的药理或外科手术调节可以稳定许多患者，但对于某些患者来说，视力仍在逐渐丧失。因此，迫切需要制定新的理性策略，以减缓或预防青光眼中发生神经元丧失。有充分的证据表明，与中枢神经系统的其他区域一样，眼睛包含内源性神经营养/神经保护因子，这些因素可限制细胞损伤。该提议的基本前提是，可以利用这些神经保护机制来防止与青光眼等疾病相关的大部分细胞死亡。该建议的重点是一个神经保护分子CNTF，这一因素已被证明在包括视网膜在内的许多CNS区域中具有有效的神经保护作用，并且是减缓神经节细胞损失进展的主要候选者。在我们的初步数据中，我们提供了证据，表明CNTF支持低密度培养物中纯化的大鼠RGC的存活，其下游效应子STAT3可阻止RGC在缺血再灌注损伤中退化。现在，我们提出了一系列实验，以测试在CNTF存在有毒水平的谷氨酸毒性水平的情况下是否可以防止RGC死亡。在第一个目标中，我们将定义CNTF用来发挥其保护作用的途径。其次，我们将检查Muller Glia是否可以通过分泌其他神经保护因素或一系列其他反应来对CNTF做出反应并为RGC提供协同保护。最后，我们将测试CNTF激活的保护途径是否通过激活线粒体解偶联蛋白而导致线粒体产生活性氧的产生。公共卫生相关性：青光眼是一种盲目疾病，影响了全球超过6500万人。仍然对导致视网膜细胞死亡和随后视力丧失的基本生化机制仍然没有很好的了解。这项研究将确定其中一些生化途径。这项研究的结果将导致鉴定可以设计新的治疗药物的靶分子。