Tiam1调控肝血窦内皮细胞参与肝损伤的分子机制研究

Liver fibrosis is the first symptom of most types of chronic liver disease, advanced liver fibrosis often results in cirrhosis, portal hypertension and liver failure. At present, there is no effective treatment for liver fibrosis, advanced cases can only be treated by liver transplantation. Therefore, it is of great significance to study the molecular mechanism of liver fibrosis and to take early intervention. Liver fibrosis is a process of liver repair in which many types of cell are involved. Liver sinusoidal endothelial cell (LSEC) plays a pivotal role in the process. T-lymphoma invasion and metastasis 1 (Tiam1) is specifically expressed in LSEC in liver, and it’s down regulated in liver injury yet its function was not known. In the early stage of liver fibrosis, LSEC would secrete large numbers of molecules that promote the growth of liver cells to reduce the process of liver fibrosis. At the same time, LSEC could dedifferentiate to a capillary state without fenestrate and forming basement membrane. The capillarization of LSEC could activate hepatic stellate cell (HSC), which would secret collagen Ⅰ to promote liver fibrosis. Thus, in this study, the molecular mechanism of Tiam1 modulating LSEC in affecting the hepatocytes behavior and activating HSC will be investigated.

肝纤维化是多种慢性肝病的前期症状，如不及时发现治疗将引发肝硬化、门静脉高压以及肝衰竭。目前，肝纤维化尚无有效的治疗方法，严重者只能通过肝移植来治疗。因此，对肝纤维化发病的分子机制研究和早期干预具有重要意义。肝纤维化是一个多细胞参与的肝脏受损修复的过程。其中， LSEC发挥了关键作用。T细胞淋巴瘤侵袭和转移因子1（Tiam1）在肝脏中特异表达于LSEC中，在肝损伤中Tiam1表达明显下调，而其作用尚未被研究。肝纤维化早期，LSEC会分泌大量促进肝细胞生长的分子，增强肝细胞的增殖减轻肝纤维化进程；同时LSEC去分化形成无窗孔、出现基底膜的毛细血管化状态，失去束缚HSC的能力，HSC因此激活分泌Collagen Ⅰ而加速肝纤维化。本研究将深入探讨Tiam1调节LSEC影响肝细胞生物学行为及HSC激活的具体分子机制。

肝纤维化是多种慢性肝病的前期症状，如不及时发现治疗将引发肝硬化、门静脉高压以及肝衰竭。目前，肝纤维化尚无有效的治疗方法，严重者只能通过肝移植来治疗。因此，对肝纤维化发病的分子机制研究和早期干预具有重要意义。肝纤维化是一个多细胞参与的肝脏受损修复的过程。T细胞淋巴瘤侵袭和转移因子1(Tiam1)在在急性肝损伤中于LSEC中表达明显下调，而其作用尚未被研究。本研究首先证实Tiam1在慢性肝损伤中特异在LSEC表达上调，并探讨了Tiam1在急性和慢性肝损伤中的动态表达变化。同时初步解释了Tiam1敲除对肝纤维化缓解的分子基础和免疫细胞招募差异。为Tiam1在肝损伤中功能的研究提供了思路和基础。