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: 10595003
• 负责人: CLAIRE H MITCHELL
• 金额: $ 46.6万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595003
• 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; cell type; combat; cytokine; extracellular; glial activation; 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.

项目概要 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 （RGC）和视力丧失是最大的危险因素。 疾病，但局部炎症信号传导也可能促成病理学。 将研究将升高的 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 小胶质细胞中的细胞因子 ͎IL-1β 将机械应变与青光眼视力丧失联系起来。 将使用星形胶质细胞比较视神经乳头星形胶质细胞的依赖性 ATP 释放 最有希望的候选者将是与机械敏感的 ATP 释放有关的缺失基因。 使用慢性高眼压症小鼠模型进行体内检查； 炎症反应或 RGC 死亡将涉及机械敏感性 ATP 释放的能力。 将在离体视网膜中探索 ATP 增强小胶质细胞迁移和 IL-1β 释放的作用 小胶质细胞以实现模型中 RGC 死亡的详细表征。 将证实IL-1β在体内杀死RGC的能力。 已证实，并测试了其对高眼压症死亡的影响。 将在体外和体内研究硬度对机械敏感 ATP 释放量的影响 最后，ATP 释放与 IL-1β 之间的联系将在视网膜中得到证实。 总之，该提案将眼压升高与人类青光眼联系起来。 这一新的假设将通过异常的嘌呤能信号来促进炎症反应。 增进我们对青光眼的了解，同时确定可能的新干预目标。

项目成果

Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis.

γ-氨基丁酸转氨酶 (GABAT) 对代谢和睡眠稳态的独立影响。

• DOI: 10.1074/jbc.m114.602276
• 发表时间: 2015
• 期刊: The Journal of biological chemistry
• 作者: Maguire,SarahE;Rhoades,Seth;Chen,Wen-Feng;Sengupta,Arjun;Yue,Zhifeng;Lim,JasonC;Mitchell,ClaireH;Weljie,AalimM;Sehgal,Amita
• 通讯作者: Sehgal,Amita