The role of glucose homeostasis during respiratory infections

项目摘要 虽然糖尿病已经达到流行病的水平，呼吸道感染，如流感，长期以来一直占据高位 世界范围内的死亡原因。糖尿病是一种持续的高血糖状态， 多器官并发症重要的是，高血糖症是糖尿病的主要和独立的危险因素。 肺部感染（包括流感感染）的发展和严重程度恶化。这种现象 认为是由于高血糖状态导致患者血糖高于正常水平 在气道中的浓度，导致肺部感染的风险增加。虽然肺是一个主要的 肺是利用葡萄糖的重要器官，但对肺内葡萄糖稳态的作用和调节研究甚少 关注因此，我们的长期目标是研究葡萄糖稳态的作用和改变， 发生在呼吸道感染时。从血液中摄取葡萄糖，限制葡萄糖利用率， 葡萄糖转运蛋白（glucose transporters，GLUT）是一种特殊的蛋白质家族。因为每个细胞 表达这些GLUT，它们被认为是全身葡萄糖代谢的主要调节剂，因此 是关键的药理学靶点。然而，人们对葡萄糖转运和利用的调控知之甚少 在呼吸系统中，特别是在高血糖状态期间。重要的是，我们最近证明， 糖尿病期间肺中几种主要的和新的GLUT同种型的表达和活性发生改变， 以及下游胰岛素信号通路。我们进一步表明，糖尿病小鼠具有更高的病毒感染率， 流感病毒感染后支气管肺泡灌洗液滴度。因此，本项目的总体目标 是了解糖尿病期间肺部葡萄糖稳态的改变如何增强病毒复制 以及流感的发病机理。本项目的具体目标是检验以下假设：1） 葡萄糖转运和利用受损增强糖尿病动物肺中的流感感染;和2） 糖尿病肺中胰岛素信号通路的改变增强了炎症反应， 流感感染的严重程度。我们将在多个系统级别使用全面的集成方法， 最先进的技术和Cobre核心设施。一个跨学科的指导小组还将提供 申请人在俄克拉荷马州丰富的智力环境中具有密集的合作研究经验 州立大学和俄克拉荷马州大学健康科学中心。从这项研究中获得的见解可以 引导我们1）在糖尿病和流感感染之间建立新的机制联系; 2）识别 病毒性流感感染的新型代谢治疗靶点，这是该项目的一项重要成果。最后通过 利用她在基础和临床科学方面的双重培训，该奖项旨在促进 申请人的发展，以实现她在呼吸和传染病领域的职业目标。

PROJECT SUMMARY While diabetes has reached epidemic levels, respiratory infections, such as influenza, have long held a high spot on the list of worldwide causes of death. Diabetes, which is defined by a persistent hyperglycemic state, leads to multiple organ complications. Importantly, hyperglycemia is a major and independent risk factor for the development and worsening severity of pulmonary infection, including influenza infection. This phenomenon is thought to occur due to the hyperglycemic state predisposing patients to a higher-than-normal glucose concentration in the airway, leading to an increased risk of pulmonary infections. Although the lung is a major organ to utilize glucose, the role and the regulation of glucose homeostasis in the lung have received little attention. Therefore, our long-term goal is to investigate the role and alterations of glucose homeostasis that occur during respiratory infections. Glucose uptake from the bloodstream, the rate-limiting in glucose utilization, is tightly regulated by a family of specialized proteins, called glucose transporters (GLUTs). Because every cell expresses these GLUTs, they are recognized as major regulators of whole-body glucose metabolism and thus are key pharmacological targets. However, little is known about the regulation of glucose transport and utilization in the respiratory system, particularly during a hyperglycemic state. Importantly, we recently demonstrated that the expression and activity of several major and novel GLUT isoforms were altered in the lung during diabetes, as well as the downstream insulin signaling pathway. We further showed that diabetic mice possess higher viral titers in the bronchial alveolar lavage fluid following influenza infection. Therefore, the overall goal of this project is to understand how alterations in pulmonary glucose homeostasis during diabetes enhance viral replication and thus the pathogenesis of influenza. The specific aims of this project are to test the hypotheses that: 1) impaired glucose transport and utilization enhances influenza infection in the lungs of diabetic animals; and 2) alterations of the insulin signaling pathway in the diabetic lung enhance the inflammatory response and the severity of influenza infection. We will use a comprehensive, integrated approach at multiple system levels using state-of-the-art techniques and the CoBRE Core Facilities. An interdisciplinary mentoring team will also provide the applicant with an intensive collaborative research experience in the rich intellectual environment at Oklahoma State University and at the University of Oklahoma Health Sciences Center. Insights gained from this study could lead us 1) to establish a novel mechanistic link between diabetes and influenza infections; and 2) to identify novel metabolic therapeutic targets for viral influenza infections, a crucial outcome of this project. Finally, by capitalizing on her strong dual training in basic and clinical sciences, this award is designed to foster the development of the applicant toward achieving her career goals in the field of respiratory and infectious diseases.