CH-ILKBP在调控足细胞结构和功能稳态中的作用及其机制研究

足细胞结构和功能损伤是多种肾小球疾病发生的中心环节。因此，阐明足细胞损伤的分子机制，探索其干预靶点具有重要意义。CH-ILKBP属于黏着斑蛋白，具有多种重要生物学功能。然而，国内外关于CH-ILKBP在足细胞损伤中的作用尚无任何报道。在本项目中，我们以足细胞敲除CH-ILKBP小鼠为模型，研究CH-ILKBP在维持足细胞结构和功能稳态中的重要作用。足细胞敲除CH-ILKBP小鼠表现出严重的肾小球损伤，包括蛋白尿、肾小球纤维化等。分子机制上，一方面我们将确认CH-ILKBP-G3BP2-TWIST1信号通路是否参与CH-ILKBP介导的足细胞损伤。另一方面，通过蛋白组学发现并确认CH-ILKBP-ZO1信号通路是否为介导足细胞损伤的新分子机制。临床上，CH-ILKBP高表达于肾小球，其表达水平可能与肾损伤严重程度相关。综上所述，本项目的开展将为发现治疗肾小球疾病的新靶点提供充分的科学依据。

Glomerular disease afflicts millions of people and imposes an enormous burden on public health-care costs worldwide. Over the past decade, many landmark studies have defined the central role of the podocyte as the determining factor in many forms of human glomerular disease, including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN) and membranous glomerulopathy. Therefore, the identification of potential therapeutic targets for preventing podocyte injury has clinical importance. CH-ILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CH-ILKBP in podocyte injury. To investigate the function of CH-ILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CH-ILKBP Neph2 cKO) was generated in which CH-ILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CH-ILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, interstitial fibrosis, protein casts was observed in CH-ILKBP Neph2 cKO mice. Mechanistically, on one hand, we identify the CH-ILKBP-G3BP2-TWIST1 signaling axis that might be critical for CH-ILKBP mediated regulation of podocytes structure and function. On the other hand, through proteomic analyses and in vitro coimmunoprecipitation, we identified ZO-1 as a novel CH-ILKBP binding protein. Thus, our results might reveal a novel signaling pathway consisting of CH-ILKBP and its mediated signaling axis that regulates podocyte structure and function. Clinically, CH-ILKBP is highly expressed in normal human glomeruli. In sum, these findings might lead to the development of novel therapeutic approaches to alleviate podocyte injury and associated glomerular diseases.