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、视网膜动脉或静脉闭塞、青光眼、