基于"失敏"机制构建的具有协同保护作用的靶向双药纳米微球对缺血性再灌注肾损伤的效果评价及机制研究

缺血再灌注肾损伤缺乏有效治疗手段。兴奋性毒性在缺血再灌注肾损伤中起重要作用，近期研究指出，阻断NMDA受体（兴奋性氨基酸受体）的及其下游死亡通路信号有望成为一种有效的治疗方法。申请者结合文献进展及预实验发现，肾缺血产生的活性氧簇可以增加细胞死亡信号对钙离子的敏感性，而减弱NMDAR阻断剂的保护作用；并提出NMDAR阻断剂（D-AP-5）联合抗氧化剂（白藜芦醇）协同保护策略。本研究将从细胞和动物两个水平进一步评价该策略的协同保护效果，并阐明协同机制。此外，半衰期短和损伤局部浓度不足是导致肾脏保护药物效果不如人意的重要原因。最新研究指出，肾缺血区存在大分子高通透和聚集现象。本研究拟在课题组前期成功构建靶向纳米递药系统的基础上，借鉴肿瘤靶向治疗成果，构建负载白藜芦醇和D-AP-5的双药纳米微球，通过其在缺血损伤区富集，实现靶向性肾保护。

Renal ischemia reperfusion (I/R) injury lack of effective treatment. Excitatory toxicity play an important role in I/R. Recent studies show that blocking NMDAR(excitatory amino acid receptor) and its downstream dead signal path will be a efficient therapy. Previous study in our lab showed that reactive oxygen species(ROS) induced by I/R could increase the cellular death sensibility to Ca2+ and counteract the protective effect of NMDAR blocker.Therefore, we propose that co-delivery of NMDAR blocker(D-AP-5) and antioxidant could generate synergistic protective effect. The current research tries to evalute the synergistic protective effects in vitro and in vivo， and elucidate the possible mechanism. Otherwise, short half-time and low concentration in the kidney are important factors of reno-protective drugs' poor effects. Recent study reported the macromolecular high permeability and retention phenomenon in I/R kidney. Through delivering resveratrol and D-AP-5 by co-loaded nanoparticles, we could protect kidney from IRI effectively.