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

项目摘要 胰腺的炎症性疾病有急性和慢性两种形式。急性胰腺炎 会导致严重疾病并缩短预期寿命。然而，除了支持性护理外，没有有效的 由于缺乏对早期细胞事件的了解而导致的疾病的治疗 这种疾病的病理生理学。慢性胰腺炎不仅糟糕，因为它不能治愈或改善，而且 只会随着时间的推移而恶化，导致胰腺的永久性损害，这也是 胰腺癌(PDAC)。与急性形式相似，这种疾病没有有效的治疗方法。 这种组织损伤导致迅速的无菌炎症反应(SIR)，其特征是水肿、免疫细胞 渗入，进一步的腺泡细胞死亡。大量证据表明，爵士在 胰腺损伤，但腺泡细胞损伤和SIR的启动之间的关键联系一直不是很好 明白了。河马信号通路以其控制器官大小、细胞增殖的能力而闻名。 和再生。值得注意的是，该通路对各种上游刺激，如机械信号， 细胞压力、细胞外刺激和黏附提示，使其成为一个很好的微环境候选者 上皮细胞在组织损伤和修复过程中协调炎症反应的传感器。 然而，河马途径在直接调节炎症反应中的作用尚未得到证实。 调查过了。我们的初步数据显示，通过敲除Lats1和Lats2而使河马途径失活， 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 未公布的数据表明，这种炎症反应并不是死亡造成的次要影响。 Lats1和2缺陷的腺泡细胞，提示河马通路具有直接调节的新功能 上皮细胞与免疫细胞的相互作用。我们假设YAP/TAZ在河马途径中介导转录- 灭活的胰腺腺泡细胞在招募和培养免疫细胞以协调 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YAP1或TAZ的表达是诱导Lats1和2中促炎基因所必需的 用遗传学方法将胰腺腺泡细胞归零。第二，我们将调查YAP和TAZ是如何 通过转录调控引起的炎症。第三，我们将测试YAP和/或Taz是 对于与急性或慢性胰腺炎相关的炎症和纤维化是必要的。我们的建议不会 只研究河马通路的新功能，但也将通过 哪些上皮细胞规定了在炎症过程中与免疫细胞的通讯。我们的研究将会有 提高对炎症性疾病病理生理学的认识 胰腺和潜在的治疗开发。

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.