The Role of Fibroblast Activation Protein in Chronic Liver Injury

慢性肝病，特别是由B型肝炎病毒和C型肝炎病毒感染引起的慢性肝病，是本港社会发病和死亡的主要原因。它们的特征是肝脏的进行性瘢痕形成，最终导致肝功能衰竭，在许多情况下需要器官移植。我们已经确定了一个关键分子成纤维细胞活化蛋白（FAP），它可能在肝纤维化（瘢痕形成）的过程中发挥关键作用。该项目的目标有四个方面：（1）确定肝脏中FAP在何处和在哪些细胞上产生，以及FAP水平是否与B肝炎或丙型肝炎病毒感染引起的人类慢性肝病中纤维化的发展相关。(2)检测FAP分子被敲除即缺失的小鼠品系。这将告诉我们FAP本身是否对纤维化的发展至关重要。(3)分离肝脏内制造FAP的细胞，并检查FAP如何改变这些细胞的特定功能。(4)为了找出FAP作用于哪些特定分子以执行其功能。这些目标的实现将大大增加我们对这种关键酶及其在慢性肝损伤中的作用的理解。这项工作可能会导致FAP功能的特异性抑制剂的开发，旨在减轻肝损伤。

Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) To characterise where and on what cells FAP is produced in the liver and whether FAP levels correlate with the development of fibrosis in human chronic liver diseases caused by either Hepatitis B or Hepatitis C virus infections. (2) To examine a mouse strain in which the FAP molecule is knocked out ie absent. This will tell us whether FAP itself is essential for the development of fibrosis. (3) To isolate the cells within the liver that make FAP and to examine how particular functions of these cells are modified by FAP. (4) To find out what particular molecules FAP acts upon to perform its functions. The achievement of these aims will greatly increase our understanding of this key enzyme and its role in chronic liver injury. This work can potentially lead to the development of specific inhibitors of FAP function designed to relieve liver damage.