The Role of Adenosine in Retinal Ischemia

描述(申请人提供)：视网膜缺血是指视网膜的氧气和葡萄糖供应中断，如视网膜血管疾病，如视网膜动脉阻塞，或由于系统性疾病，如糖尿病。病理生理学涉及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中，已经获得了广泛的生化、功能、结构和视网膜血流动力学证据，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，还证实了视网膜缺血预适应的现象，即在较长时间的缺血前24或72h的短暂非损伤性缺血完全保留了视网膜的功能和形态，防止了缺血后视网膜血流量的下降。腺苷、蛋白激酶C(PKC)、钾ATP通道和从头合成蛋白参与了这种内源性保护现象。拟议的实验将使用生化、功能和形态测量来研究腺苷启动缺血预适应的机制，蛋白激酶C的作用，以及连接腺苷、细胞核和预适应的信号媒介。该项目的长期目标是进一步表征视网膜对缺血损伤的内源性保护机制，并最终利用这些知识开发临床相关的视网膜缺血性疾病的治疗策略。 第一个目标将表征早期触发事件、信号转导因素以及腺苷在启动预适应中的作用。第二个特征是PKC的参与，以及它与腺苷在神经保护中的相互作用。第三部分将研究缺血预适应对蛋白质磷酸化的影响，表征预适应中的一些主要分子中介，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临床上有用的视网膜缺血性疾病的治疗。

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.