The Role of Adenosine in Retinal Ischemia

视网膜动脉或静脉阻塞的视网膜缺血，青光眼， 动脉粥样硬化，或糖尿病等系统性疾病。发病机制涉及到的变化 细胞生化和能量水平、血液流动和基因表达。 在这个项目的过去11年里，我们记录了广泛的生化、功能、结构和 血液动力学证据的复合体，但主要参与嘌呤核苷腺苷在 视网膜缺血再灌注损伤。最近，我们还发现了密切相关和戏剧性的 在体视网膜对缺血损伤的完整功能和组织保护作用 短暂的非损伤性缺血，即缺血预适应(IPC)。其他重要的 IPC的伴随保护机制包括抑制低灌注率、蛋白质 磷酸化和细胞凋亡。我们证明了腺苷是IPC的触发物，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， 在这种神经保护中，有丝分裂原激活的蛋白激酶p38、一氧化氮和活性氧物种。 这些令人兴奋的结果扩展了我们早期关于显著的功能和组织保护的发现 抗缺血损伤，表明IPC对细胞信号转导有深远的影响 生死存亡。在我们建立的视网膜缺血模型中检测IPC的发生机制 为了解视网膜对抗缺血损伤的内源性能力提供了一个独特的创新窗口。 第一个目标将描述IPC的信号通路，涉及线粒体KATP通道和 相关的信号转导因子。第二个目标将描述一氧化氮合酶和 PKC亚型在IPC中作为重要的信号中介。第三个目标将研究 瞬时MAPK p38的表达保护视网膜而其阻断之前的矛盾效应 缺血对缺血损伤具有保护作用。我们的实验将明确地检验主要的机制 IPC，并将使我们更接近于理解这一强大、耐人寻味和 临床相关的神经保护。

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.