疾病遗传相关的lncRNA参与狼疮肾炎发生的作用机制研究

Dysregulation or dysfunction of some key moleculars in signaling pathway is involved in disease pathogenesis. Non-coding RNA (ncRNA), as a regulator of gene expression, plays great role in signaling pathway. NcRNA includes long non-coding RNA (lncRNA) and small ncRNAs, such as microRNA. My research work recently focuses on dissecting the role of non-coding RNA in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). The main achievements are made sponsored by the National Natural Science Foundation of China (30700734, PI), the National High Technology Research and Development Program of China (863 Program, 2007AA02Z123, Co-PI) and the Program of the Shanghai Commission of Science and Technology (grant 07ZR14130, PI): 1) Our study has identified that functional variation in miR-146a promoter contributes to underexpression of miR-146a in lupus, resulting in abnormal activation in the type I IFN pathway in lupus patients by targeting the key signaling proteins (Plos genetics. 2011; Arthritis Rheum. 2009. Evaluated by Faculty of 1000 Medicine). 2) MicroRNA-125a negatively regulated RANTES expression by targeting KLF13 in activated T cells (Arthritis Rheum. 2010).3) Underexpression of miR-31 contributes to the abnormal production of IL-2 in lupus T cells via its targeting of RhoA, which results in altered nuclear NF-AT expression and IL2 promoter activity (Arthritis Rheum. 2012). Many reports in recent years have shown that lncRNA is involved in the X-chromosome silencing, genome imprinting, chromatin modification, transcriptional activation, transcriptional interference and nuclear transporting regulations. lncRNA may play great roles in pathogenesis of lupus. Based on data of RNA-seq, GWAS and preliminary study, we hypothesize that TCONS_00426627 mediated the role the lupus related SNP in inflammatory injuries of lupus nephritis. In this project, we will use lose-of-function and gain-of-function strategy to demonstrate the function of TCONS_00426627. Combined with RNA-pull down, RIP and CHIRP system, we expect to elucidate the molecular regulatory network and explore the molecular regulatory mechanism of TCONS_00426627. This project, for the first time, identifies the role of lncRNA in the organ damage of SLE disease. The expected results of this project will contribute to a better understanding of lncRNA involved in autoimmune disease and lay the foundation for understanding the pathogenesis of autoimmune diseases and developing novel therapeutic strategy.

非编码RNA在基因表达调控中有着重要作用，其表达调控网络紊乱参与了人类疾病的发生发展。我们聚焦于研究非编码RNA在系统性红斑狼疮等自身免疫病中的作用，发现了miRNA表达异常参与狼疮发生的多个环节。最近的研究工作证实了长链非编码RNA参与狼疮相关炎症因子的表达调控。本项目从疾病受累原位组织中异常表达的长链非编码RNA入手，研究长链非编码RNA在狼疮肾炎组织炎症损伤中的作用。基于RNA测序、GWAS和前期预实验结果提出如下假说：在狼疮患者中，功能性的遗传变异可导致TCONS_00426627在组织中过度表达，从而导致炎症通路的过度激活，参与疾病的组织病理损伤过程。本项目拟通过功能获得和功能缺失策略，结合转录调控、信号传导和分子相互作用研究来解析长链非编码RNA介导的遗传易感位点参与疾病组织炎症损伤的机制。本项目的预期成果将有利于揭示狼疮重要脏器受累的机制，为发展特异性的防治策略打下基础。

非编码RNA在基因表达调控中有着重要作用，其表达调控网络紊乱参与了人类疾病的发生发展。本项目从疾病受累原位组织中异常表达的长链非编码RNA入手，研究长链非编码RNA在狼疮肾炎组织炎症损伤中的作用。取得了以下主要研究进展：.1）NEAT1通过影响MAPK通路的激活调控一类LPS诱导的炎症因子的表达。在SLE病人中，过度表达的NEAT1可能是导致病人体内一些细胞因子和趋化因子增强的因素。2）在狼疮患者中，功能性的遗传变异可导致linc00513在组织中过度表达，linc00513通过影响I型干扰素信号通路下游基因的表达，从而在狼疮发病机制中起调控作用。3）长链非编码RNA RP11-2B6.2在狼疮性肾炎中是I型干扰素信号通路的正相调节分子，参与狼疮性肾炎的发病机制，并可能成为潜在的治疗靶点。.本项目的成果有利于揭示狼疮重要脏器受累的机制，为发展特异性的防治策略打下基础。

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