The Role of Adenosine in Retinal Ischemia

视网膜动脉或静脉阻塞中的视网膜缺血，青光眼， 动脉粥样硬化或全身性疾病如糖尿病。其发病机制包括 细胞生物化学和能量水平、血流和基因表达。 在过去的11年里，我们记录了大量的生物化学，功能，结构和功能。 血液动力学的证据复杂，但主要涉及嘌呤核苷腺苷， 视网膜缺血再灌注损伤最近，我们还发现了与之密切相关的 在体内视网膜中发现完全的功能和组织学保护免受缺血性损伤 由短暂的非损伤性局部缺血，即，缺血预处理（IPC）。其他重大 IPC的伴随保护机制包括减轻低灌注、蛋白质合成和细胞凋亡。 磷酸化和凋亡。我们证明了腺苷是IPC的触发器，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， 丝裂原活化蛋白激酶p38，一氧化氮和活性氧，在这种神经保护。 这些令人兴奋的结果扩展了我们早期的发现，即显著的功能和组织学保护， 从IPC提供的缺血性损伤，表明IPC对细胞信号传导有深远的影响， 生存在我们建立的视网膜缺血模型中检查负责IPC的机制 提供了一个独特的和创新的窗口，视网膜的内源性能力，以对抗缺血性损伤。 第一个目标将描述IPC的信号通路，包括线粒体KATP通道， 相关的信号转导因子。第二个目标将描述NOS参与的特点， PKC亚型是IPC中重要的信号传导媒介。第三个目标是审查 瞬时MAPK p38表达保护视网膜的矛盾效应，而在视网膜缺血前阻断MAPK p38表达， 局部缺血可防止局部缺血性损伤。我们的实验将明确地研究 IPC，并应使我们更接近了解这一强大的，有趣的， 临床相关的神经保护作用。

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.