Mechanisms of Pancreatic Fibrosis

摘要 反复或长期的胰腺损伤会导致正常的外分泌和内分泌组织的丧失 胰腺纤维化。胰腺纤维化，可导致胆总管和胰腺狭窄 导致管道阻塞的管道。重要的是，胰管梗阻可能导致 即使在没有其他胰腺损伤的情况下，也会发生慢性胰腺炎。例如，增加了 胰管压力本身会导致慢性胰腺炎和胰腺纤维化。因此，它看起来 胰腺可以感知压力和压力，这会导致胰腺损伤。 活化的胰星状细胞沉积细胞外基质导致的胰腺纤维化 (PSCS)。在正常情况下，PSCs以静止状态驻留在胰腺中，但会转化为 胰腺受损时的活跃状态。激活的PSCs分泌胶原和其他蛋白质导致 纤维化症。胰管梗阻和压力本身可导致胰腺纤维化的观察 即使在没有炎症的情况下，这也让我们不禁要问，PSCs是否能感觉到压力？如果是这样的话，是如何做到的？ 最近的发现，压力敏感性可以通过机械激活的细胞表面传递 离子通道使我们研究了胰腺中的这些蛋白质。我们最近发现，机械的- 激活的离子通道Piezo1在PSCs中高表达。我们的初步数据显示压力 胰腺的敏感性是由Piezo1传递的，Piezo1的激活可能与PSC的激活有关。 因此，我们假设胰腺内压力通过刺激引起胰腺纤维化。 PIEZO1在胰腺星状细胞(PSCs)中表达。在目前的提案中，我们将确定这条路径是否为 胰管梗阻与胰腺纤维化的联系机制。我们相信这些研究将确定 胰腺纤维化发生的新机制。此外，我们将确定是否阻止 机械激活的离子通道及其信号通路对胰腺纤维化有保护作用。总的来说， 该项目将对胰腺纤维化的启动有新的见解，并可能揭示一个新的靶点 预防其并发症。

Abstract Repeated or prolonged injury to the pancreas leads to loss of normal exocrine and endocrine tissue and pancreatic fibrosis. Fibrosis of the pancreas which can lead to stricturing of the common bile and pancreatic ducts with resultant duct obstruction. Importantly, pancreatic duct obstruction may contribute to the development of chronic pancreatitis even in the absence of other pancreatic injury. For example, increased pancreatic duct pressure itself can cause chronic pancreatitis and pancreatic fibrosis. Therefore, it appears that the pancreas can sense pressure and pressure causes pancreatic injury. Pancreatic fibrosis results from the deposition of extracellular matrix by activated pancreatic stellate cells (PSCs). Under normal conditions PSCs reside in the pancreas in a quiescent state but are converted to an active state when the pancreas is injured. Activated PSCs secrete collagen and other proteins to cause fibrosis. The observation that pancreatic duct obstruction and pressure, itself, can induce pancreatic fibrosis even in the absence of inflammation, led us to ask if PSCs can sense pressure? And if so, how? The recent discovery that pressure sensitivity could be conveyed through cell surface, mechanically-activated ion channels led us to examine these proteins in the pancreas. We recently discovered that the mechanically- activated ion channel Piezo1 is highly expressed in PSCs. Our preliminary data indicate that pressure sensitivity in the pancreas is conveyed by Piezo1 and that Piezo1 activation may be linked to PSC activation. Therefore, we hypothesize that pressure within the pancreas causes pancreatic fibrosis by stimulating Piezo1 in pancreatic stellate cells (PSCs). In the current proposal, we will determine if this pathway is the mechanism linking pancreatic duct obstruction with pancreatic fibrosis. We believe these studies will identify a novel mechanism for the development of pancreatic fibrosis. Moreover, we will determine if blocking mechanically activated ion channels and their signaling pathways protect against pancreatic fibrosis. Overall, this project will yield novel insights into the initiation of pancreatic fibrosis and could unveil a novel target for preventing its complications.