蛋白激酶D3（PKD3)调控巨噬细胞极化参与肝脏纤维化发生发展的分子机制研究

肝脏巨噬细胞（macrophage，Mϕ）是调控肝纤维化进展的关键，针对肝脏Mϕ极化的调控已成为肝纤维化治疗的潜在靶标。然而，调控肝脏Mϕ极化的分子机制尚不完全清楚。项目组前期研究发现蛋白激酶D3（PKD3）在肝脏Mϕ高表达，Pkd3全身性敲除小鼠和髓系组织特异性敲除小鼠均呈现自发性肝纤维化，并且巨噬细胞M2亚型标志物显著增多，提示Pkd3缺失可能促进Mϕ的M2极化而诱发肝纤维化。本项目将进一步研究Pkd3缺失导致肝脏自发性纤维化和参与病理性肝纤维化的作用机制，深入探索PKD3调控巨噬细胞极化的功能和分子机制。研究结果可望阐明PKD3调控巨噬细胞极化而维持肝脏内环境稳态以预防肝纤维化的作用机制，拓展对巨噬细胞极化调控肝纤维化的作用机制的认识，为巨噬细胞成为肝纤维化预防和治疗的靶标提供新证据，新靶点。

Chronic liver diseases can progress to fibrosis and cirrhosis, which is a significant cause of worldwide morbidity and mortality. The M2 polarization of macrophage (Mϕ) plays a crucial role in liver fibrosis progression and reversal.However, the signals that determine fibrogenic vs. fibrinolytic macrophage function remain ill-defined. Our previous studies show that Protein Kinase D3 (PKD3) specifically expressed in the hepatic Mϕ, and we uncovered that deletion of Pkd3 induced spontaneous fibrosis in general Pkd3 knockout mice as well as in macrophage-specific Pkd3 deletion mice, with hepatic Mϕ were increased and activated to M2-polarization dramatically. This project will further study the mechanism of Pkd3 deficiency leading to spontaneous fibrosis and whether it aggravated progression promoting of liver fibrosis in CCL4 induced liver fibrosis model in Pkd3-/- mice as well as in macrophage-specific Pkd3 deletion mice. Furthermore, to explore the function and molecular mechanism of PKD3 regulation of macrophage polarization. These study will reveal an unexpected and specific role for PKD3 in regulating macrophage polarization during liver fibrosis and have important implications for understanding the processes and mechanism of liver fibrosis.