The Role of Adenosine in Retinal Ischemia

腺苷在视网膜缺血中的作用

• 批准号: 6801809
• 负责人: STEVEN ROTH
• 金额: $ 38.13万
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801809
• 关键词: adenosine; adenosine triphosphate; blood flow measurement; disease /disorder model; electroretinography; high performance liquid chromatography; histopathology; immunocytochemistry; ischemia; ischemic preconditioning; laboratory rat; mitogen activated protein kinase; neuroprotectants; neurotransmitter metabolism; oxygen consumption; phosphorylation; potassium channel; protein biosynthesis; protein kinase C; purinergic receptor; reperfusion; retina circulation; retina disorder; terminal nick end labeling; western blottings

DESCRIPTION (provided by applicant): Retinal ischemia occurs when the oxygen and glucose supply to the retina is interrupted, as in retinal vascular diseases, such as retinal artery occlusion, or as a result of systemic diseases such as diabetes mellitus. The pathophysiology involves changes in cellular biochemistry or energy level, blood flow, and gene expression. During the first eight years of this project, extensive biochemical, functional, structural and retinal hemodynamic evidence has been obtained to support the major, but complex involvement of the purine nucleoside adenosine in retinal ischemia-reperfusion injury. In addition, the phenomenon of retinal ischemic preconditioning was demonstrated, whereby a brief period of non-damaging ischemia 24 or 72 h before more prolonged ischemia completely preserved retinal function and morphology, and prevented post-ischemic decreases in retinal blood flow. Adenosine, protein kinase C (PKC), potassium ATP channels, and de novo protein synthesis are involved in this endogenous protective phenomenon. Proposed experiments will use biochemical, functional and morphological measurements to examine the mechanisms whereby adenosine initiates ischemic preconditioning, the role of protein kinase C, and the signal mediators linking adenosine, the cell nucleus, and preconditioning. The long-term goal of the project is to further characterize the endogenous protective mechanisms against ischemic injury in the retina, and ultimately use this knowledge to develop clinically relevant treatment strategies of retinal ischemic diseases. The first aim will characterize early triggering events, signal transduction factors, and the role of adenosine in initiating preconditioning. The second characterizes the involvement of PKC, and its interaction with adenosine in this neuroprotection. The third will examine the effect of ischemic preconditioning on protein phosphorylation, characterize some of the major molecular intermediaries in preconditioning, and the relationship between these factors and adenosine. The powerful effects of endogenous neuroprotection suggest that these experiments could lead directly to clinically useful treatments for retinal ischemic diseases.

描述（由申请人提供）：视网膜缺血发生在视网膜中断的氧气和葡萄糖供应时，例如视网膜血管疾病（例如视网膜动脉闭塞）或由于糖尿病等全身性疾病的结果。病理生理学涉及细胞生物化学或能级，血流和基因表达的变化。在该项目的前八年中，已经获得了广泛的生化，功能性，结构和视网膜血流动力学证据，以支持嘌呤核苷腺苷在视网膜缺血再灌注损伤中的主要但复杂的参与。此外，还证明了视网膜缺血性预处理的现象，从而在较长的长期缺血完全保存的视网膜功能和形态上，短期无损缺血，并防止视网膜血流中缺血后降低。腺苷，蛋白激酶C（PKC），钾ATP通道和从头蛋白质合成涉及这种内源性保护现象。提出的实验将使用生化，功能和形态测量值来检查腺苷引发缺血性预处理，蛋白激酶C的作用以及连接腺苷，细胞核和预处理的信号介体的作用的机制。该项目的长期目标是进一步表征视网膜中缺血性损伤的内源性保护机制，并最终利用这些知识来开发视网膜缺血性疾病的临床相关治疗策略。 第一个目标将表征早期触发事件，信号转导因子以及腺苷在启动预处理中的作用。第二种是PKC的参与以及其与腺苷相互作用在该神经保护中的相互作用。第三个将检查缺血性预处理对蛋白质磷酸化的影响，在预处理中表征了一些主要的分子中间人，以及这些因素与腺苷之间的关系。内源性神经保护的强大作用表明，这些实验可能直接导致视网膜缺血性疾病的临床有用的治疗方法。