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

胰腺腺泡细胞中的LAP样非典型自噬及其在急性胰腺炎病理生理学中的作用

基本信息

批准号：
MR/T002220/1
负责人：
Alexei Tepikin
金额：
$ 76.49万
依托单位：
University of Liverpool
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT002220%2F1
关键词：
LAP like non canonical autophagy

项目摘要

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.

急性胰腺炎是一种常见的胰腺炎症性疾病，目前尚无特异性治疗方法。了解这种疾病的细胞和分子机制对治疗的发展至关重要。急性胰腺炎发病的早期事件与胰腺腺泡细胞损伤有关。这些细胞分泌消化酶的前体（酶原）。在生理条件下，酶原在肠道中被激活并参与消化。然而，在急性胰腺炎的早期阶段，消化酶的前体在胰腺内被不适当地激活，形成活性蛋白酶（分解蛋白质的酶），破坏腺泡细胞。胰蛋白酶是参与这一过程的重要蛋白酶。我们认为发生这种情况是因为在分泌过程中并非所有胰蛋白酶原都从腺泡细胞中释放出来，一些被称为内吞液泡的大囊泡带回到细胞中（这些囊泡获得了激活胰蛋白酶原并形成活性胰蛋白酶的能力）。目前的项目是由我们发现内吞液泡经历一种不寻常的自噬形式而发起的。自噬是细胞降解和再利用细胞成分的过程。双膜结合自噬体的形成是典型自噬的标志。许多参与这一过程的蛋白质是已知的，并被用来识别自噬体；LC3就是这样的蛋白质之一。最近，另一种涉及LC3的降解细胞机制被确定，并被称为LC3相关吞噬（LAP）。我们的初步实验结果表明，胰腺腺泡细胞的内吞空泡发生类似LAP的非典型自噬，而不是典型自噬。这一发现提示了胰腺腺泡细胞中胰蛋白酶原激活的新机制。根据这一意想不到的发现，我们计划描述这种lap样非典型自噬在急性胰腺炎中的作用，并阐明参与这一过程的分子机制。lap样非典型自噬与细胞内胰蛋白酶原激活和胰腺腺泡细胞损伤/死亡的相关性将是我们进一步研究的重点。该项目将涉及利物浦大学和东安格利亚大学的合作实验室。申请人的相关专业知识包括：LAP和自噬研究的转基因模型的开发，先进的光学和电子显微镜技术，分子生物学技术以及在急性胰腺炎评估方面的丰富经验。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Circulating monocytes in acute pancreatitis.

急性胰腺炎中循环单核细胞。

DOI：
10.3389/fimmu.2022.1062849
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Autophagy, Acute Pancreatitis and the Metamorphoses of a Trypsinogen-Activating Organelle.

DOI：
10.3390/cells11162514
发表时间：
2022-08-12
期刊：
CELLS
影响因子：
6
作者：
Voronina, Svetlana;Chvanov, Michael;De Faveri, Francesca;Mayer, Ulrike;Wileman, Tom;Criddle, David;Tepikin, Alexei
通讯作者：
Tepikin, Alexei

Polarity of action in salivary gland acinar cells: Local and preferential Ca2+ signalling.

唾液腺腺泡细胞的作用极性：局部和优先的 Ca2 信号传导。