Mechanisms of Pancreatic Fibrosis

胰腺纤维化的机制

基本信息

批准号：
10118457
负责人：
Rodger A. Liddle
金额：
$ 35.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10118457
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 pressure prevent receptor response stellate cell

项目摘要

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期损伤会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，胰管阻塞可能会导致即使没有其他胰腺损伤，也会发生慢性胰腺炎。例如，增加了胰管受压本身可引起慢性胰腺炎和胰腺纤维化。因此，看来胰腺可以感知压力，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（PSC）。正常情况下，PSC 以静止状态驻留在胰腺中，但会转化为当胰腺受伤时处于活跃状态。激活的 PSC 会分泌胶原蛋白和其他蛋白质，从而引起纤维化。胰管阻塞和压力本身可诱发胰腺纤维化的观察即使没有炎症，我们不禁要问 PSC 是否能够感知压力？如果是这样，怎么办？最近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 Piezo1 在 PSC 中高度表达。我们的初步数据表明，压力胰腺的敏感性由 Piezo1 传递，并且 Piezo1 激活可能与 PSC 激活相关。因此，我们推测胰腺内的压力通过刺激胰腺纤维化胰腺星状细胞 (PSC) 中的 Piezo1。在当前的提案中，我们将确定该途径是否是胰管阻塞与胰腺纤维化的机制。我们相信这些研究将确定胰腺纤维化发展的新机制。此外，我们将确定是否阻塞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，该项目将对胰腺纤维化的起始产生新的见解，并可能揭示一个新的靶标预防其并发症。