Purines and the Health of Retinal Ganglion Cells

嘌呤与视网膜神经节细胞的健康

基本信息

批准号：
9211326
负责人：
CLAIRE H MITCHELL
金额：
$ 29.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211326
关键词：
Acute Age Animals Astrocytes Axon Blindness Brain Cell Death Cell model Cells Chronic Chronic Disease Custom Cytokine Activation Cytoskeleton Data Disease Eye Gene Activation Genes Glaucoma Goals Health In Vitro Inflammasome Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-6 Intervention Knockout Mice Lead Link Mechanics Membrane Messenger RNA Modeling Molecular Mus Mutation Neurodegenerative Disorders Neurons Optic Disk Optic Nerve Pathogenesis Pathologic Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Physiologic Intraocular Pressure Predisposition Process Proteins Purines Research Retina Retinal Ganglion Cells Risk Risk Factors Rodent Role Route Series Signal Pathway Signal Transduction Stress Stretching Testing Time Up-Regulation base cell injury channel blockers cytokine design extracellular in vitro Model in vivo in vivo Model injured insight neuron loss novel novel strategies novel therapeutic intervention patch clamp pressure prevent public health relevance receptor response retinal damage tool

项目摘要

DESCRIPTION (provided by applicant): Glaucoma is a major cause of blindness worldwide and is characterized by a series of pathological changes to optic nerve head astrocytes and retinal ganglion cells that eventually lead to vision loss. While the biggest risk factor for cell injury is elevated intraocular pressure (IOP), proinflammatory cytokines also contribute to the chronic disease. The mechanisms connecting physical strain to the cytokine response are unclear, however. This proposal is based upon the novel hypothesis that extracellular ATP links mechanical strain to the enhanced cytokine response in glaucoma. In particular, the mechanosensitive release of ATP through pannexin channels on optic nerve astrocytes can autostimulate adjacent P2X7 receptors, upregulating cytokine expression on a molecular level and activating cytokine release through both the inflammasome and classic release pathways. Using in vivo models of elevated IOP and in vitro models of cell stretch, we will demonstrate the mechanisms linking strain and inflammation and identify points of intervention. Aim 1 will confirm the involvement of cytokines IL-1� and IL-6 in models of chronic and acute glaucoma. The time course of cytokine activation will be determined and the relative contribution of proinflammatory signals in older animals will be assessed. The contribution of pannexin and P2X7 channels will be explored on a molecular level with knockout mice, and on a pharmacological level with channel blockers; the ability of antagonists to reduce inflammasome activation may identify new treatments. In Aim 2, the mechanisms connecting mechanical strain, ATP and cytokines will be confirmed in optic nerve head astrocytes while the effects of inflammasome product IL-1� on retinal ganglion cell health will be determined. In summary, this proposal will demonstrate that purinergic signaling links elevated IOP with the enhanced inflammatory response in astrocytes and pathology in retinal ganglion cells. This novel approach will advance our understanding of the disease on a mechanistic level while identifying possible new targets for intervention.

描述（申请人提供）：青光眼是世界范围内导致失明的主要原因，其特征是视神经乳头星形胶质细胞和视网膜神经节细胞发生一系列病理变化，最终导致视力丧失，同时细胞损伤的最大危险因素升高。然而，眼内压（IOP）、促炎性细胞因子也会导致慢性疾病，但将物理应变与细胞因子反应联系起来的机制尚不清楚。特别是青光眼中细胞因子反应的增强，通过视神经星形胶质细胞上的 pannexin 通道机械敏感地释放 ATP，可以自动刺激邻近的 P2X7 受体，在分子水平上上调细胞因子的表达，并通过炎症体和经典释放途径激活细胞因子的释放。眼压升高的体内模型和细胞拉伸的体外模型，我们将证明应变和炎症之间的联系机制，并确定干预点，目标 1 将确认细胞因子的参与。慢性和急性青光眼模型中的 IL-1� 和 IL-6 将被确定，并且将评估老年动物中促炎信号的相对贡献。在分子水平上用基因敲除小鼠，在药理学水平上用通道阻滞剂；拮抗剂减少炎症小体激活的能力可能会确定新的治疗方法，将在视觉上证实连接机械应变、ATP 和细胞因子的机制。总之，该提案将证明嘌呤能信号传导将眼压升高与星形胶质细胞炎症反应增强和视网膜神经节细胞病理学联系起来。一种新方法将增进我们对这种疾病机制的理解，同时确定可能的新干预目标。