CERS6在足细胞结构和功能稳态中的作用及其机制的研究

足细胞损伤是肾小球疾病发生发展的关键因素。对正常足细胞结构、功能以及分子机制的阐明是揭示足细胞损伤机制的基础。脂筏对维持足细胞结构和功能具有重要作用，而神经酰胺合成酶CERS家族及其产物神经酰胺参与脂筏的形成及其功能；神经酰胺还能转变为S1P，再通过S1PRs受体激活ERK、PI3K、AKT，PLC等信号通路。我们前期基于肾小球单细胞RNA-seq研究，发现CERS6可能是维持足细胞的结构与功能稳态的必需基因；还发现CERS6是CERS家族中唯一在足细胞特异表达的成员，并在FSGS、DN和LN等肾小球疾病中下调。基于以上研究，我们提出研究假说：CERS6通过调节足细胞脂筏结构和S1P信号通路维持足细胞结构和功能的稳态，其表达下调促进足细胞损伤。本研究将通过体外和体内实验证明这一假说，可望加深对足细胞生物学以及损伤分子机制的了解，为肾小球病的防治提供新的靶点。

Podocyte injury is key event that underlies the development of glomerular diseases.The understanding of podocyte structure and function and the underlying molecular mechanism is the basis to elucidate the mechanism of podocyte injury. Lipid rafts are essential for podocyte structure and function, and it is known that ceramide synthases and their products, sphingolipids are involved in the formation and function of lipid rafts;sphingolipids can be converted into S1P which can serve as a ligand to act on its receptor S1PRs to activate downstream pathways, including ERK、PI3K、AKT、PLC and RAS.Based on our earlier study on single-cell RNA-seq analysis of mouse glomeruli, we found that CERS6 is likely essential for podocyte structure and function,that CERS6 is the only members of the family that is expressed specifically in podocytes, and that it is downregulated in multiple glomerular diseases, including FSGS、diabetic nephropathy and lupus nephropathy.Therefore, we hypothesize that CERS6 acts to maintain structural and functional homeostasis of podocytes through regulating lipid raft stability as well as S1P signaling pathway and that downregulation of CERS6 would facilitate podocyte injury. In the present study, we will test this hypothesis using in vitro cell culture and animal models. We expect our studies will provide insights into podocyte biology and injury, and possibly uncover a novel target for the treatment of glomerular diseases.