通过基因敲除小鼠和斑马鱼模型探究ASK3缺失对血压昼夜节律和足细胞功能的影响

膜性肾病的发病机制不明，有遗传背景、环境因素和免疫机制共同参与。我们前期研究发现在一家族性膜性肾病的家系中发现了ASK3（Apoptosis signal-regulating kinase 3）基因的移码突变，尚无该基因突变与膜性肾病的相关报道。ASK3基因自2012年被命名，相关研究较少。目前证实ASK3通过WNK1-SPAK/OSR1-NCC/NKCC通路调节远端小管对钠重吸收，参与容量和血压调控。ASK家族中ASK1是钟控基因，ASK3位于钟控基因NCC的上游，故也是潜在的钟控基因。本研究拟通过临床遗传学探究ASK3基因突变是否为膜性肾病的致病基因；通过ASK3基因敲除小鼠，观察在小管上皮细胞缺失ASK3时，足细胞对阿霉素和自身抗体诱导的损伤与野生型相比是否具有易感性，探讨小管和小球之间的crosstalk；并通过ASK3基因敲除斑马鱼模型，探索ASK3基因对尿钠和肾脏固有钟基因系统的影响。

The pathogenesis of membranous nephropathy is unknown, which involves genetic background, environmental factors and immune mechanism. Our previous study found that ASK3 (Apoptosis signal-regulated kinase 3) gene mutation was found in a familial membranous nephropathy, and no relative report associated with membranous nephropathy. ASK3 gene has been named since 2012. It has been confirmed that ASK3 regulates sodium reabsorption by distal tubules through WNK1-SPAK/OSR1-NCC/NKCC pathway, and participates in volume and blood pressure regulation. ASK1 is a clock-controlled gene in the ASK family. ASK3 is located upstream of the clock-controlled gene NCC, so it is also a potential clock-controlled gene. The purpose of this study is to explore whether ASK3 gene mutation is a pathogenic gene of membranous nephropathy through clinical genetics study; to observe whether podocytes are susceptible to adriamycin-induced and autoantibody-induced podocyte damage when ASK3 gene is knockout in tubular cell compared with wild-type mice; to explore crosstalk between tubules and glomeruli through ASK3 gene zebrafish knockout model; to explore the effect of ASK3 gene on circadian rhythm of urinary sodium excretion and kidney-specific clock system.