LAP-like non-canonical autophagy in pancreatic acinar cells and its role in the pathophysiology of acute pancreatitis

点击翻译按钮获取中文摘要

Acute pancreatitis is a frequent inflammatory disease of pancreas for which there is currently no specific treatment. Understanding cellular and molecular mechanisms of this disease is essential for the development of therapy. The early events in the initiation of acute pancreatitis are associated with damage to pancreatic acinar cells. These cells secrete precursors of digestive enzymes (zymogens). In physiological conditions zymogens are activated in the intestine and participate in digestion. However, at the early stage of acute pancreatitis precursors of digestive enzymes are inappropriately activated inside the pancreas forming active proteases (enzymes which break down proteins) that damage the acinar cells. Trypsin is an important protease involved in this process. We consider that this happens since not all trypsinogen is released from the acinar cell during secretion and some is taken back into the cell in large vesicles termed endocytic vacuoles (which acquire the ability to activate trypsinogen and form the active trypsin). The current project was initiated by our finding that endocytic vacuoles undergo an unusual form of autophagy. Autophagy is the process that allows a cell to degrade and reutilise cellular components. Formation of double membrane-bounded autophagosomes is a hallmark of well-characterised 'canonical' autophagy. Many proteins involved in this process are known and utilized to identify autophagosomes; LC3 is amongst such proteins. Recently, another degradative cellular mechanism involving LC3 was identified and termed LC3-associated phagocytosis (LAP). The results of our preliminary experiments suggest that endocytic vacuoles in pancreatic acinar cells undergo non-canonical autophagy similar to LAP rather than canonical autophagy. This finding suggests a novel mechanism of injurious trypsinogen activation in pancreatic acinar cells. Following this unexpected finding we are planning to characterise the role of such LAP-like non-canonical autophagy in acute pancreatitis and to elucidate the molecular mechanism(s) involved in this process. The relevance of LAP-like non-canonical autophagy to intracellular trypsinogen activation and damage/death of pancreatic acinar cells will be a further focus of our study. The project will involve collaborating laboratories from the University of Liverpool and University of East Anglia. Combined relevant expertise of the applicants includes: development of transgenic models for studies of LAP and autophagy, advanced optical and electron microscopy techniques, molecular biology techniques and considerable experience in evaluation of acute pancreatitis.