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.

视网膜缺血可能导致视网膜动脉或静脉闭塞，青光眼，青光眼，明显的视觉丧失，， 动脉粥样硬化，或全身性疾病（例如糖尿病）。发病机理涉及变化 细胞生物化学和能级，血流和基因表达。 在该项目的过去11年中，我们记录了广泛的生化，功能，结构和 血液'动态证据表明复合物，但嘌呤核苷腺苷的主要参与 视网膜缺血再灌注损伤。最近，我们还发现了密切相关和戏剧性的 在体内视网膜中发现完全功能和组织学保护免受缺血性损害 由短暂的无损缺血（即缺血预处理（IPC））赋予。其他重要 IPC的伴随保护机制包括衰减，蛋白质的衰减 磷酸化和凋亡。我们证明了Adeno-'Sine是IPC的触发因素，我们开始 发现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，有丝分裂原活化的蛋白激酶p38，一氧化氮和活性氧。 这些令人兴奋的结果扩展了我们对非凡功能和组织学保护的早期发现 来自IPC造成的缺血性损害，表明IPC对细胞信号传导和 生存。检查我们已建立的视网膜缺血模型中负责IPC的机制 为视网膜的内源性能力抵抗缺血性损伤提供了独特而创新的窗口。 第一个目标将表征涉及线粒体KATP通道的IPC的信号传导途径和 相关的信号转导因子。第二个目标将表征NOS和 PKC亚型是IPC中必需的信号中介机构。第三个目标将检查 瞬态的MAPK p38表达式保护视网膜的矛盾效应，而其封锁 缺血可预防缺血性损害。我们的实验将确定检查的主要机制 IPC，应该使我们更加了解这种强大，有趣和的分子事件 临床相关的神经保护。