The Hippo signaling pathway in pancreatic epithelial cells orchestrate the inflammatory response R01

胰腺上皮细胞中的 Hippo 信号通路协调炎症反应 R01

• 批准号: 9311258
• 负责人: Pei Wang
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311258
• 关键词: Acinar Cell; Acute; Address; Adhesions; Adult; Cause of Death; Cell Communication; Cell Cycle; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Stress; ChIP-seq; Chronic; Communication; Complement; Cues; Data; Disease; Edema; Epithelial; Epithelial Cells; Event; Fibrosis; Functional disorder; Genes; Genetic Transcription; Human; Immune; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knock-out; Knockout Mice; Life Expectancy; Link; Mechanics; Mediating; Mus; Natural regeneration; Null Lymphocytes; Organ Size; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Diseases; Pancreatitis; Pathogenesis; Pathway interactions; Phenotype; Phosphotransferases; Play; Positioning Attribute; Prevention; Property; Reaction; Recruitment Activity; Regulation; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Sterility; Stimulus; Stress; Supportive care; Testing; Therapeutic; Time; Tissues; Transcription Coactivator; Transcriptional Regulation; Tumor Suppressor Genes; Up-Regulation; acute pancreatitis; cell injury; chronic pancreatitis; connective tissue growth factor; cytokine; effective therapy; extracellular; genetic approach; improved; injury and repair; insight; mouse model; novel; novel strategies; repaired; response; sensor; therapeutic development; transcriptome sequencing

Project Summary The inflammatory disorders of the pancreas have two forms, acute and chronic. Acute pancreatitis causes severe illness and reduces life expectancy. However, besides supportive care, there is no effective treatment for the disease due to a lack of understanding of the early cellular events important in the pathophysiology of this disease. Not only is chronic pancreatitis as bad in that it does not heal or improve and only gets worse over time leading to permanent damage of the pancreas, it is also the top risk factor for pancreatic adenocarcinoma (PDAC). Similar to the acute form, there is no effective treatment for this disease. This tissue damage causes a rapid sterile inflammatory response (SIR) characterized by edema, immune cell infiltration, and further acinar cell death. A lot of evidence points towards the SIR having a vital role in pancreatic damage, but the crucial link between acinar cell injury and initiation of the SIR has not been well understood. The Hippo signaling pathway is best known for its ability in controlling organ size, cell proliferation and regeneration. Noticeably, this pathway responds to various upstream stimuli such as mechanical signals, cellular stress, extracellular stimuli and adhesion cues, making it a good candidate as a microenvironment sensor for epithelial cells to orchestrate the inflammatory response during tissue injury and repair. Nevertheless, the role of the Hippo pathway in directly regulating inflammatory reactions has not been investigated. Our preliminary data showed that inactivation of the Hippo pathway by knocking out Lats1&2, specifically in acinar cells, rapidly induced the inflammatory response in the pancreas. Notably, our unpublished data indicated that this inflammatory response was not the secondary effect caused by the death of Lats1&2 deficient acinar cells, suggesting the novel function of the Hippo pathway to directly regulate epithelial-immune cell interactions. We hypothesize that YAP/TAZ mediated transcription in Hippo pathway- inactivated pancreatic acinar cells plays important roles in recruiting and educating immune cells to orchestrate the inflammatory response. Our hypothesis will be tested with three specific aims. First, we will test the hypothesis that expression of YAP1 or TAZ are necessary for induction of pro-inflammatory genes in Lats1&2 null pancreatic acinar cells using a genetic approach. Second, we will investigate how YAP and TAZ induce inflammation through transcriptional regulation. Third, we will test the hypothesis that Yap and/or Taz are necessary for the inflammation and fibrosis associated with acute or chronic pancreatitis. Our proposal will not only investigate the novel functions of Hippo pathways, but will also address the fundamental mechanisms by which epithelial cells specify the communication with immune cells during inflammation. Our research will have important implications to improve understanding of the pathophysiology of inflammatory diseases in the pancreas and for potential therapeutic development.

项目摘要 胰腺炎性疾病有两种形式，急性和慢性。急性胰腺炎 会导致严重疾病并缩短预期寿命。然而，除了支持性治疗， 由于缺乏对早期细胞事件的了解， 这种疾病的病理生理学。慢性胰腺炎不仅不好，因为它不愈合或改善， 随着时间的推移只会变得更糟，导致胰腺的永久性损伤，这也是最大的风险因素， 胰腺癌（PDAC）。类似于急性形式，没有有效的治疗方法。 这种组织损伤引起快速的无菌炎症反应（SIR），其特征是水肿、免疫细胞减少和炎症反应。 浸润和进一步的腺泡细胞死亡。许多证据表明，SIR在以下方面发挥着至关重要的作用： 胰腺损伤，但腺泡细胞损伤和启动SIR之间的关键联系还不清楚 明白Hippo信号通路以其控制器官大小、细胞增殖 和再生。值得注意的是，这条通路对各种上游刺激做出反应，如机械信号， 细胞应激，细胞外刺激和粘附线索，使其成为一个很好的候选人作为微环境 上皮细胞的传感器，以协调组织损伤和修复期间的炎症反应。 然而，Hippo通路在直接调节炎症反应中的作用还没有被证实。 研究了我们的初步数据显示，通过敲除Lats 1和Lats 2， 特别是在腺泡细胞中，迅速诱导胰腺的炎症反应。值得注意的是，我们的 未发表的数据表明，这种炎症反应不是死亡引起的继发性效应， Lats 1和2缺陷腺泡细胞，这表明Hippo通路的新功能是直接调节 上皮-免疫细胞相互作用。我们推测雅普/TAZ介导的Hippo通路的转录- 失活的胰腺腺泡细胞在募集和训练免疫细胞以协调 炎症反应。我们的假设将通过三个具体目标进行检验。首先，我们将测试 假设YAP 1或TAZ表达是诱导Lats 1和2中促炎基因所必需的 用遗传学方法去除胰腺腺泡细胞。其次，我们将研究雅普和TAZ如何诱导 炎症通过转录调节。第三，我们将测试假设，雅普和/或塔兹是 与急性或慢性胰腺炎相关的炎症和纤维化所必需。我们的建议不会 我们只研究Hippo通路的新功能，但也将通过以下方式解决基本机制： 哪些上皮细胞在炎症期间指定与免疫细胞的通信。我们的研究将有 重要的意义，以提高对炎症性疾病的病理生理学的理解， 胰腺和潜在的治疗发展。