Der Toll-like Rezeptor-TRIF Signaltransduktionsweg in der akuten Pankreatitis

急性胰腺炎Toll样受体-TRIF信号转导通路

• 批准号: 178712425
• 负责人: Professor Dr. Christoph Michalski
• 金额: --
• 依托单位: Klinik und Poliklinik für Chirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/178712425?language=en
• 关键词: Der; Toll; like; Rezeptor; TRIF

Acute pancreatitis (AP) is a potentially lethal disease often involving peripancreatic tissues and sometimes affecting distant organs. The severity of the disease depends on the extent and type of acinar cell death: while induction of apoptosis ameliorates AP, its inhibition worsens the disease. During AP, detection of endogenous factors (“danger” signals) released from “stressed” cells might be conferred by Toll-like receptors (TLRs) either on acinar cells themselves, on neighboring cells or on immune cells. In a preliminary set of experiments, severity of pancreatitis was strikingly worsened and increased pancreatic tissue necrosis was observed in mice lacking the common signaling adaptor protein of TLR3 and TLR4, the Toll/interleukin-1 receptor domain-containing adaptor protein, TRIF. In this project proposal, we aim at elucidating whether these observed effects are due to a direct TRIF function in acinar cells, are indirectly due to modulation of immune cell responses or both. We propose as a new concept that TRIF functions as a gatekeeper between apoptosis and necrosis in pancreatic acinar cells. Thus, TRIF may control local inflammation during acute pancreatitis and perpetuation of a systemic inflammatory response.

急性胰腺炎（AP）是一种潜在致命的疾病，通常累及胰周组织，有时影响远处器官。疾病的严重程度取决于腺泡细胞死亡的程度和类型：虽然诱导细胞凋亡可改善 AP，但抑制细胞凋亡会使疾病恶化。在 AP 过程中，对“应激”细胞释放的内源因子（“危险”信号）的检测可能由 Toll 样受体 (TLR) 赋予腺泡细胞本身、邻近细胞或免疫细胞。在一组初步实验中，在缺乏 TLR3 和 TLR4 共同信号转接蛋白（含有 Toll/interleukin-1 受体结构域的转接蛋白 TRIF）的小鼠中，观察到胰腺炎的严重程度显着恶化，并且胰腺组织坏死增加。在本项目提案中，我们旨在阐明这些观察到的效应是否是由于腺泡细胞中的直接 TRIF 功能所致，还是间接由于免疫细胞反应的调节所致，或两者兼而有之。我们提出了一个新概念：TRIF 在胰腺腺泡细胞凋亡和坏死之间发挥着看门人的作用。因此，TRIF 可以控制急性胰腺炎期间的局部炎症和全身炎症反应的持续。