Purines and the health of retinal ganglion cells

项目摘要 青光眼是导致失明的主要原因，其特征是视网膜神经节细胞死亡。 (RGCs)和视力丧失。高眼压(IOP)是导致眼压升高的最大危险因素 疾病，但局部炎症信号也可能导致病理。这项建议 将研究高眼压与局部炎症信号和RGC之间的联系 死亡，基于创新的假设，即依赖于ATP的炎症释放 来自小胶质细胞的细胞因子͎IL-1β将机械劳损与青光眼的视力丧失联系起来。伸展- 将使用星形胶质细胞比较视神经头星形胶质细胞的依赖性ATP释放 与机械敏感的ATP释放有关的基因缺失。最有希望的候选人将 使用慢性高眼压的小鼠模型进行活体检查；降低 炎症反应或RGC死亡将牵连机械敏感性的ATP释放。一种能力 将探索三磷酸腺苷促进小胶质细胞迁移和IL-1β释放的作用 小胶质细胞，以实现详细的特征描述。模型中对RGC死亡的贡献 慢性高眼压的诊断将得到证实。IL-1β在体内杀伤视网膜神经节细胞的能力将是 确认了其对高眼压患者死亡的影响。底物的影响 对机械敏感的ATP释放大小的僵硬将在体外和在 活着。最后，三磷酸腺苷释放和IL-1β之间的联系将在视网膜中得到证实。 患有青光眼的人类。总而言之，这项提议将把高眼压与 通过异常的嘌呤能信号引起的促炎反应。这一新颖的假说将 促进我们对青光眼的理解，同时确定可能的新干预靶点。

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.