脂蛋白相关的磷脂酶A2（Lp-PLA2）是一个由炎症细胞分泌的蛋白，广泛参与血管壁的一系列炎症反应,曾经作为心血管、老年痴呆和糖尿病视网膜病变的药物研发靶标。经过多年的Lp-PLA2抑制剂研究，我们的药理实验发现我们的第二代高活性Lp_PLA2抑制剂VL2可以显著的抑制ZDF糖尿病大鼠的微量白蛋白尿，改善糖尿病肾病症状。因此引出的未曾被关注的科学问题：Lp-PLA2如何与糖尿病肾病发病相关？Lp-PLA2有可能成为治疗糖尿病肾病的药物靶标吗？如何优化Lp-PLA2抑制剂来获得更好的治疗糖尿病肾病药效？本项目将采用模型动物药理试验、药效和药代的结构优化、生化组织分析以及数据集成处理等手段，对Lp_PLA2抑制剂是否能够成为以及怎样成为治疗糖尿病肾病的候选新药进行深入的研究.

Lipoprotein associated phospholipase A2 (Lp_PLA2) which is secreted by immune cells involves a series of inflammatory responses in vascular wall, so it has been considered as the targets for drug development on atherosclerosis、Alzheimer’s disease and diabetic retinopathy. After many years’ research we found compound VL2, the second generation of our high potent Lp_PLA2 inhibitor, can significantly reduce the microalbuminuria and ameliorate of diabetic nephropathy of ZDF rats after 6 weeks oral treatment. So the scientific questions arise for: (1) what is the correlation between Lp_PLA2 and diabetic nephropathy? (2) Can Lp_PLA2 become a target for drug discovery on diabetic nephropathy? (3) How to optimize the structure of Lp_PLA2 inhibitor to gain better efficacy for treatment diabetic nephropathy on animal model? This project tries to answer those questions after a set of studies including pharmacological tests in ZDF rats, structure- activity and structure- pharmacokinetics optimizations, kidney tissue morphology and biochemical research and also the data integration and analysis.