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：
8651585
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651585
关键词：
Acute Age Animals Astrocytes Axon Blindness Brain Cell Death Cells Cessation of life Chronic Chronic Disease Custom Cytokine Activation Cytoskeleton Data Disease Eye Gene Activation Genes Glaucoma Goals Health In Vitro 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 Pathology Pathway interactions Pharmaceutical Preparations Physiologic Intraocular Pressure Predisposition Process Proteins Purines Relative (related person)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 neuronal transport novel novel strategies novel therapeutic intervention novel therapeutics patch clamp pressure prevent public health relevance purine receptor response tool

项目摘要

Project Summary 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.

项目摘要青光眼是全球失明的主要原因，其特征是视神经头星形胶质细胞和视网膜的一系列病理变化有时会导致视力丧失的神经节细胞。而最大的风险因素细胞损伤是眼内压（IOP），促炎细胞因子也是有助于慢性疾病。将物理压力连接到的机制但是，细胞因子反应尚不清楚。该建议基于细胞外ATP将机械应变与增强的新假设青光眼中的细胞因子反应。特别是，机械敏感的释放通过视神经星形胶质细胞上的pannexin通道ATP可以自动刺激相邻的P2X7受体，分子水平上的细胞因子表达上调并通过炎症和经典激活细胞因子释放释放途径。使用升高IOP和体外模型的体内模型细胞拉伸，我们将演示连接应变和炎症的机制并确定干预点。 AIM 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。时间课程将确定细胞因子激活，并相对贡献将评估老年动物的促炎信号。的贡献 Pannexin和P2X7通道将在分子水平上探索，并进行敲除小鼠，在具有通道阻滞剂的药物水平上；能力减少炎性体激活的拮抗剂可以鉴定新的治疗方法。在 AIM 2，连接机械应变，ATP和细胞因子的机制将是在视神经头星形胶质细胞中确认，而炎性体的影响将确定视网膜神经节细胞健康的产物IL-1。总而言之，这提案将证明嘌呤能信号链接升高IOP与残留神经节中星形胶质细胞和病理学的炎症反应增强细胞。这种新颖的方法将提高我们对疾病的理解机械水平同时确定可能的新目标进行干预。