IgA肾病（IgAN）是最常见的肾小球肾炎，全基因组关联分析发现MTMR3遗传变异与其发病相关，但具体机制不清。MTMR3是自噬负调控基因，其反向功能分子Vps34敲除后导致肾炎。我们前期工作发现，MTMR3是IgAN及狼疮性肾炎的共同致病基因；足细胞自噬在自身抗体和I型干扰素介导的肾损伤中起保护作用，雷帕霉素上调自噬减轻足细胞损伤。我们提出假说：MTMR3参与IgAN遗传易感性；MTMR3表达或功能上调、导致自噬受损、促进肾脏损伤；细胞特异性抑制MTMR3可能为IgAN治疗靶点。本项目拟开展精细定位研究，明确在疾病人群基因型-细胞表型、免疫表型的关联；进而进行细胞学和细胞特异性MTMR3干预小鼠模型实验，明确MTMR3-自噬引起IgAN肾损伤的机制及相关信号途径；最后探讨抑制MTMR3的作用和疗效。研究有望深化自噬与IgAN发病机制的认识，为寻找新的治疗靶点提供线索。

IgA nephropathy (IgAN) is the most common glomerulonephritis in China. Of these patients, 20%-40% develop end-stage renal disease (ESRD) requiring renal replacement therapy over 10-20 years. Current diagnosis and treatment is mainly based on clinical symptoms and histological description, which do not necessarily reflect underlying pathophysiology or provide information on prognosis. MTMR3 gene region has been associated with susceptibility to IgAN by all the GWASs conducted in IgAN, but the precise pathophysiological mechanism is still obscure. MTMR3 is responsible for PI3P metabolism involved in autophagy initiation, whereas PI3P production is under tight control of PI3Kinase, hVps34. Gene knock-out of Vps34 will lead to early onset of nephropathy. Our previous study indicated that MTMR3 gene variants associated with both IgAN and lupus nephritis. We also observed that podocyte autophagy is cytoprotective in renal injury induced by auto-antibodies and interferon-a. Rapamycin could induce autophagy showing therapeutic role in LN. We hypothesize that MTMR3 genetic variants associated with immune related nephritis; apart from immunological effect, it is involved in impaired renal resident cell autophagy renal injury; cell specific MTMR3 inhibition may be a novel target in therapy. To validate it, we will conduct genetic fine-mapping analysis to check the relationship between causal variant and specific clinical, cell and molecular phenotypes in human patients with IgAN; further we will use the established IgAN mice model as well as cell-specific Vps34 knock-out mice to check the pathogenic role of MTMR3/Vps34 in autophagy and renal injury; at last, we will explore if MTMR3 inhibition will be comparable to Rapamycin in efficacy and more specific in treatment of IgAN. Our project will provide new evidence of autophagy in etiology and progression of IgAN, and may shed new therapeutic target.