端粒缩短触发NLRP3/TGF-beta/Smad3信号通路对IgA肾病重症进展的调控研究

IgA肾病发病机制尚不明确。端粒功能缺陷常见于人类衰老和慢性疾病过程中。我们前期研究发现端粒损伤导致中性粒细胞衰老后释放LL37与IgA肾病进展相关；端粒缩短中性粒细胞衰老处理后共培养可显著上调系膜细胞NLRP3、TGF-beta的表达。提示端粒损伤中性粒细胞衰老后释放LL37，激活NLRP3，进而激活TGF-beta/Smad3信号通路，促进IgA肾病进展。本课题拟通过比较健康对照组、轻重症IgA肾病的肾脏组织病理、端粒功能、LL37、NLRP3/TGF-beta/Smad3分子信号通路的差异表达；并利用端粒缺陷小鼠、NLRP3敲除小鼠、端粒缺陷和NLRP3双敲除小鼠IgA肾病模型，明确LL37通过激活NLRP3，上调TGF-beta的表达和分泌而促进IgA肾病进展。本研究可明确端粒缩短触发TGF-beta/Smad3信号通路在IgA肾病重症进展中的作用，为临床诊治提供提供新靶点。

The pathogenesis of IgA nephropathy is not clear. Telomere defects are common in human aging and chronic diseases. Our previous study found that telomere injury led to the release of LL37 after neutrophil senescence, which was associated with the progression of IgA nephropathy; telomere-shortening neutrophil senescence co-culture can significantly up-regulate the expression of NLRP3、TGF-beta in.mesangial cells. It is hypothesis that LL37, by activating NLRP3 and upregulating TGF-beta/Smads signaling in kidney tissue, promotes the progression of IgA nephropathy. This topic intends to compare the pathology of renal tissue, telomere function, and the differential expression of LL37 and NLRP3/TGF-beta /Smad3 signaling pathways among the healthy control group, mild to severe IgA nephropathy patients. In use of telomere-deficient mice, NLRP3 knockout mice, Telomere defects and NLRP3 double knockout mouse model of IgA nephropathy, it is to make clear that LL37 promotes the progression of IgA nephropathy by activating NLRP3 and promoting the expression and secretion of TGF-beta. This study could clarify the mechanism of telomere shortening in triggering the TGF-beta signaling pathway in the severe progression of IgA nephropathy, and provide a new target for clinical diagnosis and treatment.