Purines and the Health of Retinal Ganglion Cells

项目摘要 青光眼是世界范围内导致失明的主要原因之一，其特征是 视神经头星形胶质细胞和视网膜的一系列病理改变 最终导致视力丧失的神经节细胞。虽然最大的风险因素是 细胞损伤是眼压升高，促炎症细胞因子也是 会导致慢性病。将身体应激与 然而，细胞因子的反应尚不清楚。这项建议是基于 新的假说认为细胞外ATP将机械应变与增强的 青光眼的细胞因子反应。特别是，机械敏感的释放 视神经星形胶质细胞上通过膜联蛋白通道的三磷酸腺苷可以自动刺激 相邻的P2X7受体在分子水平上上调细胞因子的表达 并通过炎症小体和经典激活细胞因子的释放 释放路径。应用体内高眼压模型和体外高眼压模型 细胞伸展，我们将演示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 IL-1β和IL-6在慢性和急性青光眼模型中的作用的时间进程 将确定细胞因子的激活和相对贡献 将对老年动物的促炎信号进行评估。的贡献 PAnnexin和P2X7通道将在分子水平上通过敲除进行探索 小鼠，并在药物水平上使用通道阻滞剂； 减少炎性小体激活的拮抗剂可能会找到新的治疗方法。在……里面 目标2，机械应变、三磷酸腺苷和细胞因子的联系机制将是 证实在视神经头星形胶质细胞的同时炎性小体的作用 产品IL-1对视网膜神经节细胞健康的影响将被测定。总而言之，这是 该提案将证明，嘌呤能信号将高眼压与 星形胶质细胞炎症反应增强与视网膜神经节病理 细胞。这一新的方法将促进我们对这种疾病的理解 在确定可能的干预新目标的同时，采取机械性的措施。

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.