Regulation and functional relevance of GLP-2 in sepsis

GLP-2 在脓毒症中的调节和功能相关性

• 批准号: 468418471
• 负责人: Professor Dr. Michael Lehrke
• 金额: --
• 依托单位: Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin (Med. Klinik I)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/468418471?language=en
• 关键词: Regulation; functional; relevance; GLP; sepsis

Systemic infection and sepsis are frequent complications of critical ill patients. In many cases no infectious focus can be found, suggesting the physiological microflora to act as an infectious source in the stressed organism. Critical illness impairs intestinal barrier function and allows translocation of microorganisms to the organism. Improvement of gut barrier function might provide a valuable strategy to prevent bacterial translocation of critical ill patients and to reduce infectious burden by sealing bacterial entry sites. In this study we are aiming to evaluate the regulation and mechanistic relevance of GLP-2 as a preproglucagon cleavage product released from the gut and the pancreas to improve gut barrier function under inflammatory conditions. In preliminary results we demonstrate marked elevation of GLP-2 levels in critical ill patients, while GLP-2 was increased in response to inflammatory stimuli in an IL6 dependent manner in mice. Using tissue specific preproglucagon expressing mice we found inflammatory GLP-2 secretion to originate from the pancreas but not from the gut. Functionally, GLP-2 application strongly modified the inflammatory response of mice challenged by colon ligation puncture (CLP) or endotoxin induced sepsis, while absence of GLP-2 in preproglucagon knockout mice caused the opposite. It is the aim of this proposal to characterise the relevance of endogenous GLP-2 secretion for inflammatory response and outcome in sepsis. In the first step we will characterize the inflammatory cascade leading to endotoxin dependent GLP-2 secretion in mice by employing preproglucagon reporter mice (Aim 1). We will then study the anti-inflammatory capacities of GLP-2 in murine sepsis by use of gain and loss of function models (Aim 2), investigate the relevance of pancreatic vs. intestinal GLP-2 production (Aim 3) and study the functional relevance of IL6 as a GLP-2 inducing stimulus in murine sepsis (Aim 4).

全身感染和败血症是重症患者的常见并发症。在许多情况下，找不到感染焦点，这表明生理菌群是压力生物体中的传染性来源。危害疾病会损害肠道屏障功能，并允许微生物转移到生物体上。肠道屏障功能的改善可能会提供一种有价值的策略，以防止细菌易生病患者的细菌易位，并通过密封细菌进入部位来减轻感染负担。在这项研究中，我们旨在评估GLP-2作为从肠道和胰腺释放的前葡萄糖裂解产物的调节和机理相关性，以在炎症条件下改善肠道屏障功能。在初步结果中，我们证明了关键病患者的GLP-2水平明显升高，而GLP-2在小鼠中以IL6依赖性的炎症刺激增加了GLP-2。使用组织特异性前葡萄糖表达小鼠，我们发现炎症性GLP-2分泌来自胰腺，但不是肠道。在功能上，GLP-2的应用强烈改变了结肠连接穿刺（CLP）或内毒素诱导的败血症所挑战的小鼠的炎症反应，而在前葡聚糖基因敲除小鼠中缺乏GLP-2会导致相反。 该提议的目的是表征内源性GLP-2分泌在败血症中的炎症反应和结果的相关性。在第一步中，我们将通过采用前葡萄糖核记者小鼠（AIM 1）来表征小鼠内毒素依赖性GLP-2分泌的炎症级联反应（AIM 1）。然后，我们将通过使用功能模型的增益和丧失（AIM 2）研究鼠败血症中GLP-2的抗炎能力（AIM 2），研究胰腺与肠道GLP-2产生的相关性（AIM 3）并研究功能性的功能性IL6作为鼠败血症中诱导刺激的GLP-2的相关性（AIM 4）。