端锚聚合酶TNKS介导的Wnt/β-catenin/炎性小体NLRP3信号轴在肾纤维化发生发展中的调控机制

Renal fibrosis, a common pathway and main pathogenic basis of end stage of all kinds of kidney disease, strongly correlates with progressive loss of renal function. Therefore, further study of molecular mechanisms of renal fibrosis is of great importance to slow and reverse the disease process. Recent studies have shown that abnormal activation of Wnt/β-catenin pathway involved in regulating renal fibrosis, but the exact mechanism is unclear. Our preliminary experiments show the expression of tankyrases (TNKS) andβ-catenin were increased in animal and cell models with fibrosis. Therefore, we hypothesis that TNKS mediate Wnt/β-catenin activation and promote renal fibrosis. We will be planning to explore the important/potential role of TNKS in regulation of Wnt/β-catenin pathway in vivo, in vitro and clinical experiments. In order to explore the downstream mechanism of β-catenin regulating renal fibrosis, inflammation and inflammasome (NLRP3) activity will be observed. Moreover, we plan to explore the effect of a specific inhibitor of TNKS (YJ976) on renal fibrosis. This study contributes to the understanding of the role of TNKS, and provides new strategies to seek for the new drugs target for treatment of renal fibrosis.

肾纤维化是各种原发或继发性肾病进展到终末期的共同途径和主要病理基础，深入研究其发病机制对延缓肾病进程具有重要意义。新近研究表明Wnt/β-catenin通路异常激活参与调控肾纤维化进程，与肾脏发育及多种肾脏病发病相关，其确切分子机制未明。我们前期研究在肾纤维化动物和细胞模型中均发现端锚聚合酶TNKS和β-catenin表达升高，小干扰RNA降调TNKS表达可抑制肾小管上皮细胞β-catenin表达。推测：TNKS调控Wnt/β-catenin的激活进而促进肾纤维化发展。本项目拟通过细胞培养、在体动物和临床病人确证TNKS调控的Wnt/β-catenin通路在肾纤维化发展中的作用及机制（炎症反应）；在此基础上进一步探讨靶向于TNKS的特异性抑制剂YJ976对肾纤维化的治疗作用。本项目首次提出TNKS可能是治疗肾纤维化的新靶点，期望为肾间质纤维化的防治提供新的思路和策略。

肾纤维化是各种原发或继发性肾病进展到终末期的共同途径和主要病理基础，深入研究其发病机制对延缓肾病进程具有重要意义。国内外对端锚聚合酶TNKS的报道多集中于肿瘤发病机制，而对其在肾纤维化中作用尚无报道。本项目通过在体动物、离体细胞和临床实验确证Wnt/β-catenin通路介导的炎症反应促进肾纤维化发生；在细胞水平进行基因抑制和过表达分析，探讨TNKS对β-catenin及炎性小体NLRP3的调控作用，揭示TNKS是治疗肾纤维化的潜在靶点，在此基础上运用靶向于TNKS的特异性抑制剂，以确证该靶点在肾纤维化疾病中的重要作用。本课题首次探讨了在肾纤维化条件下，TNKS对Wnt/β-catenin通路的激活作用。首次从炎症反应角度，探讨Wnt/β-catenin/炎性小体NLRP3轴调控促进肾纤维化进程的病理生理机制。同时，本项目研究TNKS的特异性抑制剂对Wnt/β-catenin通路的作用，可为纤维化疾病的治疗提供新思路和新药靶。