The Role of Adenosine in Retinal Ischemia

描述（由申请人提供）：视网膜动脉或静脉阻塞、青光眼、动脉粥样硬化或全身性疾病（如糖尿病）中的视网膜缺血可能导致严重视力丧失。发病机制涉及细胞生物化学和能量水平、血流和基因表达的变化。 在过去的11年中，我们记录了大量的生物化学，功能，结构和血液动力学证据的复杂，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的和引人注目的发现，即在体内视网膜中由短暂的非损伤性缺血所赋予的完全功能和组织学保护免受缺血性损伤，即，缺血预处理（IPC）。IPC的其他重要伴随保护机制包括减轻低灌注、蛋白磷酸化和细胞凋亡。我们证明了腺苷是IPC的触发剂，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、促分裂原活化蛋白激酶p38、一氧化氮和活性氧在这种神经保护中的作用。这些令人兴奋的结果扩展了我们早期的发现，即IPC对缺血性损伤具有显著的功能和组织学保护作用，表明IPC对细胞信号传导和存活具有深远的影响。在我们建立的视网膜缺血模型中检查负责IPC的机制为视网膜对抗缺血性损伤的内源性能力提供了独特和创新的窗口。 第一个目标将表征IPC涉及线粒体KATP通道和相关信号转导因子的信号通路。第二个目标将表征参与NOS和PKC亚型作为IPC中的重要信号中介。第三个目标将研究矛盾效应的机制，即瞬时MAPK p38表达保护视网膜，而缺血前对其的阻断则保护视网膜免受缺血性损伤。我们的实验将明确研究IPC的主要机制，并使我们更接近于理解这种强大的，有趣的和临床相关的神经保护的分子事件。

DESCRIPTION (provided by applicant): 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 hemodynamic 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 adenosine 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 pathways for 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.