The Role of Adenosine in Retinal Ischemia

描述（由申请人提供）：当视网膜的氧气和葡萄糖供应中断时，视网膜缺血发生，如视网膜血管疾病，如视网膜动脉闭塞，或由于全身性疾病，如糖尿病。病理生理学包括细胞生化或能量水平、血流和基因表达的变化。在这个项目的前八年里，广泛的生化、功能、结构和视网膜血流动力学证据已经获得，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，研究还证实了视网膜缺血预处理现象，即在更长时间缺血前24或72小时的短暂无损伤性缺血完全保留了视网膜功能和形态，并防止了缺血后视网膜血流量的减少。腺苷、蛋白激酶C （PKC）、钾ATP通道和从头蛋白合成参与了这种内源性保护现象。拟议的实验将使用生化，功能和形态学测量来检查腺苷启动缺血预处理的机制，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质。该项目的长期目标是进一步表征视网膜缺血性损伤的内源性保护机制，并最终利用这些知识制定视网膜缺血性疾病的临床相关治疗策略。

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.