WFS1蛋白调控醛固酮合成的作用及机制研究

醛固酮瘤的核心病理生理特征为自主（过度）醛固酮分泌，其患者的心脑血管并发症显著增加。醛固酮瘤中醛固酮合成的调控机制尚未完全阐明。我们前期通过4D蛋白质组学发现醛固酮瘤中WFS1的表达显著增高；进一步功能实验证实：在HAC15细胞中过表达WFS1可显著增加其醛固酮合成；后续干预实验提示WFS1可能通过三磷酸肌醇受体促进内质网钙离子流入胞浆，激活钙离子信号通路，调控醛固酮合成。基于前期基础，本项目拟开展以下研究：1）通过肾上腺特异性WFS1高表达的小鼠模型，以及WFS1高/低表达的HAC15细胞和醛固酮瘤原代细胞，明确WFS1对醛固酮合成的调控作用；2）利用siRNA、抑制剂干预和蛋白质免疫共沉淀等多种实验手段，阐明WFS1调控醛固酮合成的分子机制；3）在已建立的醛固酮瘤样本库中，对WFS1相关通路进行再验证。本研究有望进一步阐明醛固酮瘤中醛固酮合成的调控机制，并为其药物治疗提供新的干预靶点。

Aldosterone producing adenoma (APA) is pathophysiologically characterized by autonomous (excessive) aldosterone secretion. The cardiovascular and cerebrovascular complications in patients with APA have increased dramatically. The regulatory mechanism of aldosterone synthesis in APA has not been fully elucidated. We previously found through 4D proteomics that the expression of WFS1 was significantly increased in APA. Further functional experiments confirmed that the overexpression of WFS1 in HAC15 cells significantly increased its aldosterone synthesis. Subsequent intervention experiments suggested that WFS1 may promote the efflux of Ca2+ from endoplasmic reticulum to cytoplasm through triphosphate inositol receptors, activating calcium signaling pathway and thus regulating aldosterone synthesis. Based on our preliminary data, this project aims to carry out the following experiments: 1) To investigate the regulatory effect of WFS1 on aldosterone synthesis through a mouse model with adrenal specific overexpression of WFS1, HAC15 cell and APA primary culture cell with over/down expression of WFS1; 2) To clarify the molecular mechanism of WFS1 in regulating aldosterone synthesis by techniques such as siRNA or inhibitor treatment and immunoprecipitation etc.; 3)To verify the WFS1-related pathways in an APA sample library established previously. This study is expected to further clarify the regulatory mechanism of aldosterone synthesis in APA and provide a novel intervention target for its medical therapy.