Mechanisms of Pancreatic Fibrosis

胰腺纤维化的机制

• 批准号: 10630177
• 负责人: Rodger A. Liddle
• 金额: $ 36.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630177
• 关键词: Acinar Cell; Agonist; Cations; Cell secretion; Cell surface; Cells; Chronic; Cicatrix; Circulation; Collagen; Common bile duct structure; Data; Deposition; Development; Duct (organ) structure; Ductal Epithelial Cell; Endocrine; Exhibits; Exocrine pancreas; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Generations; Genetic; Gland; Inflammation; Injury; Investigation; Ion Channel; Islet Cell; Link; Malignant neoplasm of pancreas; Mechanics; Mediating; Modeling; Molecular; Mus; Natural regeneration; Nuclear; Obstruction; Pancreas; Pancreatic Injury; Pancreatic duct; Pathogenesis; Pathway interactions; Physiological; Piezo 1 ion channel; Proteins; Reaction; Recurrence; Retinoids; Risk; Role; Signal Pathway; Source; Tissues; acute pancreatitis; chronic pancreatitis; direct application; injured; insight; islet; mechanical force; novel; novel therapeutics; pancreas development; pancreatic juice; pancreatic stellate cell; pressure; prevent; protective pathway; receptor; response; stellate cell

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.

摘要 胰腺的反复或长期损伤导致正常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 导致导管阻塞的导管。重要的是，胰管梗阻可能有助于 即使在没有其他胰腺损伤的情况下，也会发生慢性胰腺炎。例如增加的 胰管压力本身可引起慢性胰腺炎和胰腺纤维化。因此， 胰腺可以感知压力，而压力会导致胰腺损伤 胰腺纤维化是由活化的胰腺星状细胞沉积细胞外基质引起的 （私营保安公司）。在正常情况下，PSC以静止状态存在于胰腺中，但转化为 胰腺损伤时的活动状态。活化的PSC分泌胶原蛋白和其他蛋白质， 纤维化胰管阻塞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，我们也会问PSC是否可以感知压力？如果是的话，怎么做？ 最近发现压力敏感性可以通过细胞表面传递，机械激活 离子通道引导我们检查胰腺中的这些蛋白质。我们最近发现机械- 激活的离子通道Piezo 1在PSC中高度表达。我们的初步数据显示 胰腺中的敏感性由Piezo 1传递，Piezo 1激活可能与PSC激活有关。 因此，我们假设胰腺内的压力通过刺激 胰腺星状细胞（PSC）中的Piezo 1。在目前的提案中，我们将确定这条途径是否是 胰管阻塞与胰腺纤维化的联系机制我们相信这些研究将确定一个 胰腺纤维化发展的新机制。此外，我们将确定是否阻止 机械活化的离子通道及其信号传导途径可防止胰腺纤维化。总的来说， 该项目将对胰腺纤维化的发生产生新的见解，并可能揭示一种新的靶点， 防止并发症。