端粒损伤触发LL37—IGF1R分子通路在IgA肾病进展作用中的研究

IgA肾病是我国最常见的慢性肾脏病，危害严重而发病机制不明。申请人前期研究发现由端粒损伤诱发分泌的特异性蛋白质，能预示衰老和慢性疾病的发生发展。从中锁定了LL37增多造成细胞衰老与IgA肾病进展相关。进一步研究后发现并提出了端粒损伤诱发分泌LL37等衰老相关因子，通过IGF1R继而激活ERK通路作用于肾脏系膜细胞等肾脏实质细胞，促使疾病进展的假说。本课题将通过生物信息学技术将IgAN患者肾脏组织RNA转录组学数据进行互作分析研究，能够推测基于前期研究的IgAN进展端粒触发LL37-IGF1R-ERK机制；然后通过细胞体外培养技术构建肾小球系膜细胞体外交叉互作培养体系，研究细胞间相互作用对疾病的影响，以及端粒、线粒体功能和相关分子机制对肾脏主要实质细胞生理、病理的调控作用。通过研究将对IgAN疾病进展分子调控机制进行全面的研究、完整的阐述，为早期诊治提供干预靶点，延缓病程，降低危

IgA nephropathy is the most common chronic kidney disease in China, with serious harm and unknown pathogenesis. The applicant's previous research found that the specific proteins induced by telomere damage can predict aging and the occurrence and development chronic diseases, which locked that increased LL37 causes cell senescence is related to the progression of IgA nephropathy. Further research puts forward the hypothesis that telomere damage promotes the progression of the disease by inducing the secretion of aging-related factors such as LL37, and then activating the ERK pathway through IGF1R on renal mesangial cells.This topic will use bioinformatics technology to mutually analyze the RNA transcriptomics data of kidney tissues of IgAN patients,which can accurately speculate the telomere-triggered LL37-IGF1R-ERK mechanism of IgAN progression based on previous studies;then through in vitro cell culture technology construct an in vitro cross-interaction culture system of glomerular mesangial cells,and study the effects of intercellular interactions on disease,as well as the regulation of telomere, mitochondrial function and related molecular mechanisms on the physiology and pathology of major renal parenchymal cells. Through the research, the molecular regulation mechanism of IgAN disease progression will be comprehensively researched and elaborated to provide intervention targets for early diagnosis and treatment, delay the course and reduce the risk of disease.