慢性肾脏病（CKD）已经成为全球性公共健康问题， CKD患者发展到终末期需要依赖血液透析维持生命，而建立透析通路的动静脉瘘手术（AVF）一年通畅率只有63%，且尚无有效防治措施。研究表明：CKD可促进平滑肌细胞（VSMCs）增殖引起血管新生内膜增生（NH），具体机制不明。有研究发现NLRP3炎症体信号通路介导VSMCs增殖/迁移，参与NH过程。还有研究发现尿毒症患者特异性修饰的低密度脂蛋白（cLDL）可激活NLRP3炎症体介导血管炎症。本课题拟应用NLRP3基因敲除小鼠，通过5/6肾脏切除术、AVF构建CKD、NH疾病模型，结合分子生物学和细胞生物学、病理学观察等技术，明确CKD患者升高的cLDL激活NLRP3炎症体，导致下游Caspase-1活化，诱导IL1β，IL18等细胞因子的成熟与分泌，引起VSMCs增殖/迁移，从而促进NH的分子机制。为治疗CKD相关NH，改善CKD预后提供靶点。

Chronic kidney disease (CKD) has become an important public health problem in the world. An arteriovenous fistula (AVF) is the method of choice for dialysis access in CKD patients with end-stage renal disease that require hemodialysis. Patients who undergo hemodialysis utilizing AVFs often need to be re-intervened surgically in order to correct stenotic lesions which compromise blood flow through the fistula. This is reflected in the fact that the one year patency rates of AVF are estimated to be only 63%. The major cause of vascular access failure in AVFs is venous stenosis due to neointimal hyperplasia (NH). However, the mechanisms underlying how CKD accelerates NH remain largely unknown. We will use molecular and cell biological technologies and pathological methods to examine these changes in surgically induced CKD and NH mouse models and NLRP3 knockout mice to test these hypothesis that: 1. CKD induces vascular smooth muscle cells (VSMC) proliferation/migration and NH via NLRP3 inflammasome activation pathway; 2. CKD uremia and uremia-elevated cLDL induce NRLP3 inflammasome assembly and Casp-1 activation and that pathway of IL-1β, IL-18 may carry out the proliferation of VSMCs. 3. Inhibition of NRLP3 inflammasome reverses CKD-accelerated NH. NLRP3 would be a potential therapeutic target for CKD associated NH.