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：
8791691
负责人：
CLAIRE H MITCHELL
金额：
$ 29.2万
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/8791691
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 purine receptor response tool

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 purine receptor response tool

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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（由适用提供）：青光眼是全球失明的主要原因，其特征是对视神经头星形胶质细胞和视网膜神经节细胞的一系列病理变化，有时会导致视力丧失。虽然最大的细胞损伤危险因素是眼内压（IOP）升高，但促炎细胞因子也会导致慢性疾病。但是，将物理应变连接到细胞因子反应的机制尚不清楚。该建议基于以下新假设：细胞外ATP将机械应变与青光眼中增强的细胞因子反应联系起来。特别是，在视神经星形胶质细胞上通过泛毒素通道的机械释放可以自aster刺激相邻的P2X7受体，在分子水平上上调细胞因子表达，并通过炎症体和经典释放途径激活细胞因子。使用IOP升高和体外细胞伸展模型的体内模型，我们将演示连接应变和注射的机制，并识别干预点。 AIM 1将证实细胞因子IL-1和IL-6在慢性和急性青光眼模型中的参与。将确定细胞因子激活的时间过程，并评估老年动物促炎信号的相对贡献。 Pannexin和P2X7通道的贡献将以敲除小鼠的分子水平以及通道阻滞剂的药物水平进行探索。拮抗剂减少炎性体激活的能力可以鉴定新的治疗方法。在AIM 2中，将在视神经头星形胶质细胞中确认连接机械应变，ATP和细胞因子的机制，而炎性体产物产物IL-1？将确定视网膜神经节细胞健康的影响。总而言之，该提案将证明嘌呤能信号与视网膜神经节细胞中星形胶质细胞和病理学的炎症反应升高联系在一起。这种新颖的方法将在机械水平上提高我们对疾病的理解，同时确定可能的新目标进行干预。