Purines and the health of retinal ganglion cells

项目摘要 青光眼是致盲的主要原因，其特征是视网膜神经节细胞的死亡 （RGC）和视力丧失。眼内压（IOP）升高是眼内炎的最大危险因素。 疾病，但局部炎症信号也可以有助于病理。这项建议 将研究IOP升高与局部炎症信号和RGC之间的联系 死亡，基于创新的假设，即ATP依赖性释放的炎症 来自小胶质细胞的细胞因子IL-1β将青光眼中的机械应变与视力丧失联系起来。伸展- 视神经头星形胶质细胞的依赖性ATP释放将使用星形胶质细胞 缺失了与机械敏感性ATP释放有关的基因。最有希望的候选人将 使用慢性高眼压的小鼠模型在体内进行检查; 炎症反应或RGC死亡将牵涉机械敏感性ATP释放。的能力 在离体视网膜中，将探讨ATP对小胶质细胞迁移和IL-1β释放的影响。 小胶质细胞，以实现详细的表征。模型中RGC死亡的贡献 慢性高眼压的可能性IL-1β在体内杀死RGC的能力将被证实。 证实，并测试其对高眼压死亡的贡献。基质效应 将在体外和体内研究刚性对机械敏感性ATP释放量的影响。 vivo.最后，ATP释放和IL-1β之间的联系将在视网膜中得到证实。 昏迷的人类。总之，该提案将IOP升高与 通过异常嘌呤能信号传导的促炎反应。这一新的假设将 进一步了解青光眼，同时确定可能的新干预目标。

Project Summary Glaucoma is a major cause of blindness, characterized by the death of retinal ganglion cells (RGCs) and loss of vision. An elevated intraocular pressure (IOP) is the biggest risk factor in the disease, but localized inflammatory signaling can also contribute to the pathology. This proposal will investigate the pathways linking elevated IOP to local inflammatory signaling and RGC death, based on the innovative hypothesis that ATP-dependent release of the inflammatory cytokine ͎IL-1β from microglial cells links mechanical strain to vision loss in glaucoma. Stretch- dependent ATP release from optic nerve head astrocytes will be compared using astrocytes missing genes implicated in mechanosensitive ATP release. The most promising candidates will be examined in vivo using a mouse model for chronic ocular hypertension; reduced levels of inflammatory responses or RGC death will implicate mechanosensitive ATP release. The ability of ATP to enhance microglial migration and IL-1β release will be explored in isolated retinal microglial cells to enable detailed characterization. The contribution to RGCs death in a model of chronic ocular hypertension will be confirmed. The ability of IL-1β to kill RGCs in vivo will be confirmed and its contribution to death in ocular hypertension tested. The effect of substrate stiffness on the magnitude of mechanosensitive ATP release will be investigated in vitro and in vivo. Finally, the links between ATP release and IL-1β will be confirmed in the retina of glaucomatous humans. In summary, this proposal will connect elevated IOP with proinflammatory responses through aberrant purinergic signaling. This novel hypothesis will advance our understanding of glaucoma while identifying possible new targets for intervention.