PLOD2调控胶原交联模式参与肝纤维化的机制研究

肝纤维化的主要特征是肌成纤维细胞（MF）分泌的以胶原为代表ECM成分的过度沉积。胶原蛋白在分泌出细胞之前需要进行一系列修饰，前胶原赖氨酸-2-酮戊二酸5-双加氧酶2（PLOD2）可催化端肽区赖氨酸残基羟基化，使得胶原纤维之间形成吡啶交联而变得难以被降解从而发生积聚。前期结果证实：在四氯化碳诱导的纤维化小鼠模型中，肝内PLOD2表达明显增加，且与MF标志物aSMA、Col I和Col III存在正相关关系。但是目前对于PLOD2在整个肝纤维化进展中的作用及确切调控机制尚不清楚。本项目以PLOD2为靶分子，以MF为研究对象，拟从整体、细胞和分子水平系统揭示肝纤维化时PLOD2通过改变MF中胶原纤维的交联模式和溶解性，进而促进肝纤维化的发生机制。利用基于抑制PLOD2的策略（PLOD2中和抗体、抑制剂、siRNA或miR-590-3p激动剂）控制胶原吡啶交联将为肝纤维化的治疗提供新思路和新靶点。

Liver fibrosis is characterized by excessive deposition of ECM component collagen secreted by myofibroblast (MF). Collagen needs a series of modifications before it is secreted into ECM. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) catalyzes the hydroxylation of lysyl residues in collagen telopeptides, making collagen more resistant to degradation thus resulting in its accumulation. Our preliminary results show that PLOD2 expression is significantly up-regulated in the fibrotic liver of carbon tetrachloride mice, and positively correlates with the expression of MF markers (aSMA, Col I and Col III). However, the role of PLOD2 in the progression of liver fibrosis and the exact regulatory mechanism are still unclear. In the present study, we investigate the critical role of PLOD2 in changing the crosslink patterns of collagen fiber and collagen degradability in MF, leading to the progression of liver fibrosis, and explore the underlying molecular mechanisms. Strategies based on blockade of PLOD2 (PLOD2 neutralizing antibody, inhibitor, siRNA or miR-590-3p agomir) to control pyridinoline crosslink of collagen fiber will provide new insights and therapeutic target for liver fibrosis.