Molecular basis of adenosine transport and reuptake inhibition in human

缺血再灌注(IR)损伤是指缺氧后组织遭受长期损伤的一种现象 氧合血液回流，证明是器官移植面临的普遍临床挑战，以及缺血 心、肺、肾疾病。最终，IR损伤可导致梗塞面积扩大、器官排斥反应和器官 失败了。嘌呤核苷腺苷是在细胞外产生的对IR损伤的反应，并引起 激动型腺苷G蛋白的心脏保护、肺保护和肾脏保护作用 偶联受体。然而，细胞外腺苷的半衰期是极其短暂的，因为 完整的膜转运蛋白介导腺苷的快速膜渗透，其中 核苷最终在胞质中代谢。人平衡核苷转运体(HENTs)是 细胞内主要的腺苷转运体。此外，腺苷再摄取抑制剂(ADORI)，一种化学上的 不同种类的hent抑制剂通过阻止腺苷的快速再摄取来增强细胞外的腺苷信号 通过hENTs。因此，精选的ADORI在心脏病的治疗中被用作血管活性物质 和肾脏疾病。然而，目前的ADORI由于其较差的临床效果而受到限制。 药理特性和毒性。一直在努力改进现有的ADORI或开发新的ADORI 面临缺乏关于hENTs和ADORI机制的原子水平信息的挑战。这项建议 研究试图通过使用分子、细胞和化学方法来解决这一知识差距 腺苷再摄取抑制、腺苷识别及其转运机制的研究 由hENTs展出。值得注意的是，新型腺苷再摄取抑制剂的合理设计显示出改进 将使用心脏和肾脏模型系统进行亚型特异性研究。这项工作将揭开分子 ADORI活性、腺苷识别以及hENTs的转运机制。在……里面 总之，这项工作的成功完成将为改进药物干预提供框架 腺苷生物学在心、肺、肾缺血治疗中的深远意义 疾病。

Ischemia-reperfusion (IR) injury is a phenomenon in which hypoxic tissue undergoes prolonged damage after the return of oxygenated blood, proving a prevalent clinical challenge faced in organ transplant, and ischemic heart, lung and kidney diseases. Ultimately, IR injury can lead to increased infarct size, organ rejection and organ failure. The purine nucleoside adenosine is produced extracellularly in response to IR injury, and elicits cardioprotective, pulmonary protective and renal protective effects through agonizing adenosine G-protein coupled receptors. However, the half-life of extracellular adenosine is extremely short-lived, as specialized integral membrane transport proteins mediate the rapid membrane permeation of adenosine, where the nucleoside is ultimately metabolized within the cytosol. Human equilibrative nucleoside transporters (hENTs) are the main cellular adenosine transporters. Furthermore, adenosine reuptake inhibitors (AdoRIs), a chemically diverse class of hENT inhibitors, potentiate extracellular adenosine signaling by preventing its rapid reuptake through hENTs. Therefore, select AdoRIs are clinically used as vasoactive agents in the treatment of cardiopathy and renal disorders. However, current AdoRIs are limited in their clinical effectiveness due to their poor pharmacological properties and toxicities. Efforts to improve current AdoRIs or develop novel AdoRIs has been challenged by the lack of atomic-level information on hENTs and the mechanism of AdoRIs. This proposed research seeks to address this gap in knowledge by employing molecular, cellular, and chemical approaches to interrogate features of adenosine reuptake inhibition, adenosine recognition and the transport mechanism exhibited by hENTs. Notably, the rational design of novel adenosine reuptake inhibitors displaying improved subtype specificity will be pursued using cardiac and renal model systems. This work will uncover the molecular features of AdoRI activity, adenosine recognition, along with the transport mechanism exhibited by hENTs. In total, successful completion of this work will provide the framework for improved pharmacological intervention of adenosine biology, which will have far-reaching implications in the treatment of ischemic heart, lung, and kidney disease.