Purines and the health of retinal ganglion cells

嘌呤与视网膜神经节细胞的健康

• 批准号: 10368131
• 负责人: CLAIRE H MITCHELL
• 金额: $ 49.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368131
• 关键词: ATP Receptors; Address; Age; American; Astrocytes; Blindness; Cell Death; Cells; Cessation of life; Chemotactic Factors; Chronic; Data; Development; Disease; Elderly; Ensure; Eye; Gel; Genes; Glaucoma; Health; Human; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Intervention; Investigation; Laboratories; Link; Mechanics; Microglia; Microspheres; Modeling; Monkeys; Mus; Neurodegenerative Disorders; Ocular Hypertension; Optic Disk; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiologic Intraocular Pressure; Process; Publishing; Purines; Rattus; Retina; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Stretching; Testing; Tissues; Vision; Work; age effect; age related; base; cell type; combat; cytokine; extracellular; in vivo; innovation; migration; mouse model; neurotoxic; nonhuman primate; novel; pressure; receptor; response

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.

项目摘要 青光眼是失明的主要原因，其特征是残留神经节细胞死亡 （RGC）和视力丧失。眼内压（IOP）是最大的风险因素 疾病，但局部炎症信号传导也可以导致病理。这个建议 将研究将升高IOP与局部炎症信号和RGC联系起来的途径 死亡，基于ATP依赖性炎症释放的创新假设 小胶质细胞的细胞因子͎IL-1β将机械应变与青光眼的视力丧失联系起来。拉紧- 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 在机械敏感的ATP释放中实现的缺失基因。最有前途的候选人将 使用小鼠模型在体内检查慢性眼高血压；降低的水平 炎症反应或RGC死亡将暗示机械敏感的ATP释放。能力 将在孤立的视网膜中探索ATP以增强小胶质细胞迁移和IL-1β释放 小胶质细胞以实现详细的表征。模型中对RGC死亡的贡献 慢性眼高血压将得到证实。 IL-1β在体内杀死RGC的能力将是 已确认及其对眼部高血压死亡的贡献。底物的效果 机械敏感ATP释放幅度的刚度将在体外和 体内。最后，将在ATP释放与IL-1β之间的联系 青光眼人类。总而言之，该建议将与 通过异常的嘌呤能信号传导产生促炎反应。这个新颖的假设将 提高我们对青光眼的理解，同时确定可能的新目标进行干预。