羟氯喹通过抑制TLR9-MTMR3-自噬通路治疗IgA肾病的机制研究

IgA肾病（IgAN）是引起终末期肾病常见原因之一，尚缺乏特异性治疗。我们前期观察性以及随机对照研究均证实羟氯喹（HCQ）可有效降低IgAN患者蛋白尿。然而，其作用机制尚不明确。IgAN发生发展过程依赖TLR9活化及下游效应；而细胞自噬参与TLR9诱导的B细胞活化和免疫球蛋白产生。我们前期研究发现，肌微管素相关蛋白3（MTMR3）参与IgAN发生，其机制可能与TLR9介导的自噬异常有关。因此，我们推测HCQ通过抑制TLR9-MTMR3-自噬通路，降低致病性IgA及炎症介质产生，发挥作用。本研究拟开展HCQ治疗IgAN患者临床和免疫表型的关联研究，探讨HCQ与TLR9激活、MTMR3-自噬通路的关系。通过细胞学实验，明确HCQ调控TLR9与自噬信号途径及调控机制。利用小鼠模型，评价HCQ发挥治疗作用的表型机制，阐明因果关系。研究有望进一步揭示IgAN致病机制、为优化治疗提供靶点和实验依据。

IgA nephropathy (IgAN) is one of the most common causes of end-stage renal disease. At present, there is no specific treatment. Our previous observational studies and randomized controlled studies have confirmed that hydroxychloroquine (HCQ) can safely and effectively reduce the proteinuria level of patients with IgAN, and play a role in the treatment of IgAN. However, the mechanism of HCQ is not clear..The development of IgAN depends on the activation and downstream effect of TLR9.Autophagy is involved in the proliferation and activation of B cells and the production of immunoglobulin induced by TLR9. Our previous studies have found that MTMR3 is involved in the development of IgAN, and its mechanism may be related to TLR9 mediated autophagy. Therefore, we speculate that HCQ may play a therapeutic role by inhibiting TLR9-MTMR3-autophagy pathway and further reducing the production of pathogenic IgA and inflammatory mediators..The purpose of this study is to investigate the relationship between HCQ and TLR9 activation, MTMR3 autophagy pathway, as well as the relationship between HCQ and inflammation. Furthermore, through cytological experiments, the mechanism of TLR9 and autophagy signal regulated by HCQ was clarified. Another purpose is to evaluate the phenotypic mechanism of the therapeutic effect of HCQ and clarify the causal relationship. The study is expected to further reveal the pathogenesis of IgAN and provide the target and experimental evidence for optimization treatment.