Mechanisms of Pancreatic Fibrosis

胰腺纤维化的机制

• 批准号: 10408830
• 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/10408830
• 关键词: Acinar Cell; Address; Agonist; Blood Circulation; Cations; Cell surface; Cells; Chronic; Cicatrix; 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; Lead; Link; Malignant neoplasm of pancreas; Mechanics; Mediating; Modeling; Molecular; Mus; Natural regeneration; Obstruction; Pancreas; Pancreatic Injury; Pancreatic duct; Pathogenesis; Pathway interactions; Physiological; Piezo 1 ion channel; Proteins; Recurrence; Retinoids; Risk; Role; Signal Pathway; Source; Tissues; acute pancreatitis; base; chronic pancreatitis; direct application; injured; insight; islet; mechanical force; novel; novel therapeutics; pancreas development; pancreatic juice; pancreatic stellate cell; pressure; prevent; 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.

抽象的 胰腺反复或长时间受伤会导致正常外分泌和内分泌组织的损失 胰腺纤维化。胰腺的纤维化可能导致普通胆汁和胰腺的限制 导管导管阻塞。重要的是，胰管阻塞可能有助于 即使在没有其他胰腺损伤的情况下，慢性胰腺炎也会发育。例如，增加 胰管压力本身会导致慢性胰腺炎和胰腺纤维化。因此，它出现了 胰腺可以感觉到压力和压力会造成胰腺损伤。 胰腺纤维化是由活化胰腺细胞在细胞外基质沉积中产生的 （PSC）。在正常条件下，PSC居住在胰状态，但被转换为 胰腺受伤时活跃状态。激活的PSC分泌胶原蛋白和其他蛋白质引起 纤维化。胰管导管阻塞和压力本身可以诱导胰腺纤维化的观察结果 即使在没有炎症的情况下，我们也会问PSC是否会感觉到压力？如果是这样，怎么样？ 最近发现，压力敏感性可以通过细胞表面传达，机械激活 离子通道使我们在胰腺中检查了这些蛋白质。我们最近发现机械 活化的离子通道压电1在PSC中高度表达。我们的初步数据表明压力 胰腺中的敏感性由压电1传达，而Piezo1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引起胰腺纤维化 胰腺星状细胞（PSC）中的压电1。在当前建议中，我们将确定此途径是否是 将胰管阻塞与胰腺纤维化联系起来的机制。我们相信这些研究将确定 胰腺纤维化发展的新机制。而且，我们将确定是否阻止 机械激活的离子通道及其信号通路可防止胰腺纤维化。全面的， 该项目将产生对胰腺纤维化开始的新见解，并可以公开一个新的目标 防止其并发症。