The Role of Adenosine in Retinal Ischemia

腺苷在视网膜缺血中的作用

• 批准号: 7385926
• 负责人: STEVEN ROTH
• 金额: $ 36.52万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385926
• 关键词: Adenosine; Apoptosis; Atherosclerosis; Biochemical; Biochemistry; Blindness; Blood flow; Complex; Diabetes Mellitus; Disease; Erythropoietin; Event; Gene Expression; Glaucoma; Injury; Ischemia; Ischemic Preconditioning; Knowledge; Lead; MAP Kinase Gene; MAPK14 gene; Mediator of activation protein; Mitochondria; Modeling; Molecular; Nitric Oxide; Nitric Oxide Synthase; Pathogenesis; Pathway interactions; Phosphorylation; Purine Nucleosides; Reactive Oxygen Species; Reperfusion Injury; Retina; Retinal; Role; Signal Transduction; Testing; Vascular Diseases; Venous; attenuation; clinically relevant; in vivo; innovation; mitogen-activated protein kinase p38; neuroprotection; research study; retinal ischemia

Significant visual loss may result from retinal ischemia in retinal arterial or venous occlusion, glaucoma, atherosclerosis, or in systemic disorders such as diabetes mellitus. The pathogenesis involves changes in cellular biochemistry and energy level, blood flow, and gene expression. During the past 11 years of this project, we documented extensive biochemical, functional, structural, and hemo-'dynamic evidence for the complex, but major involvement of the purine nucleoside adenosine in retinal ischemia-reperfusion injury. More recently, we also discovered the closely related and dramatic finding of complete functional and histological protection from ischemic damage in the in vivo retina conferred by a brief period of non damaging ischemia, i.e., ischemic preconditioning (IPC). Other significant accompanying protective mechanisms of IPC include the attenuation of hypoperfusion, protein phosphorylation, and apoptosis. We demonstrated that adeno-'sine is a trigger for IPC, and we began to uncover the roles of downstream signal transduction factors, including mitochondrial KATP channels, PKC, mitogen-activated protein kinase p38, nitric oxide, and reactive oxygen species, in this neuroprotection. These exciting results extend our earlier findings of the remarkable functional and histological protection from ischemic damage afforded by IPC, indicating that IPC has a profound influence upon cell signaling and survival. Examination of the mechanisms responsible for IPC in our established retinal ischemia model provides a unique and innovative window into the retina's endogenous ability to counter ischemic injury. The first aim will characterize the signaling pathwaysfor IPC involving mitochondrial KATP channels and the associated signal transduction factors. The second aim will characterize the involvement of NOS and PKC subtypes as essential signaling intermediaries in IPC. The third aim will examine the mechanisms of the paradoxical effect whereby transient MAPK p38 expression protects the retina, while its blockade prior to ischemia protects against ischemic damage. Our experiments will definitively examine major mechanisms of IPC and should bring us closer to understanding molecular events underlying this robust, intriguing, and clinically relevant neuroprotection.

严重的视力丧失可能是由于视网膜动脉或静脉阻塞、青光眼、视网膜缺血、 动脉粥样硬化，或糖尿病等全身性疾病。发病机制涉及以下方面的变化 细胞生物化学和能量水平、血流量和基因表达。 在该项目过去 11 年中，我们记录了广泛的生化、功能、结构和 血流动力学证据表明嘌呤核苷腺苷复杂但主要参与 视网膜缺血再灌注损伤。最近，我们还发现了密切相关且戏剧性的 发现体内视网膜具有完整的功能和组织学保护，免受缺血性损伤 由短暂的非破坏性缺血（即缺血预适应（IPC））赋予。其他重要的 IPC 的伴随保护机制包括减弱灌注不足、蛋白质 磷酸化和细胞凋亡。我们证明了腺苷是 IPC 的触发因素，并且我们开始 揭示下游信号转导因子的作用，包括线粒体 KATP 通道、PKC、 在这种神经保护作用中，丝裂原激活蛋白激酶 p38、一氧化氮和活性氧。 这些令人兴奋的结果扩展了我们早期关于卓越的功能和组织学保护的发现 免于 IPC 造成的缺血性损伤，表明 IPC 对细胞信号传导具有深远的影响， 生存。在我们建立的视网膜缺血模型中检查 IPC 的机制 为了解视网膜抵抗缺血性损伤的内源性能力提供了一个独特且创新的窗口。 第一个目标是描述涉及线粒体 KATP 通道的 IPC 信号传导途径和 相关的信号转导因子。第二个目标将描述 NOS 的参与和 PKC 亚型作为 IPC 中重要的信号中介。第三个目标将研究机制 短暂的 MAPK p38 表达可以保护视网膜，而其阻断之前的作用是矛盾的 缺血可以防止缺血性损伤。我们的实验将明确检查主要机制 IPC 应该使我们更深入地了解这种强大的、有趣的和潜在的分子事件 临床相关的神经保护。