The role of glucose homeostasis during respiratory infections

葡萄糖稳态在呼吸道感染期间的作用

• 批准号: 10459263
• 负责人: VERONIQUE A LACOMBE
• 金额: $ 18.53万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459263
• 关键词: Adult; Affect; Age; Animals; Attention; Award; Basic Science; Beta Cell; Bioenergetics; Blood Circulation; Cause of Death; Cells; Clinical Sciences; Communicable Diseases; Core Facility; Death Rate; Development; Diabetes Mellitus; Diabetic mouse; Diffusion; Disease; Energy Metabolism; Environment; Epidemic; Epithelial; Epithelial Cells; Excision; Exhibits; Family; Fostering; Glucose; Glucose Transporter; Goals; Health Sciences; Human; Hyperglycemia; Impairment; In Vitro; Incidence; Inflammatory; Inflammatory Response; Influenza; Insulin; Insulin Receptor; Insulin Signaling Pathway; Interferon Type II; Interleukin-6; Knockout Mice; Lead; Link; Lung; Lung Lavage Fluid; Lung infections; Measures; Mediating; Mentors; Messenger RNA; Metabolic; Metabolism; Mitochondria; Mus; Oklahoma; Organ; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Permeability; Pharmacology; Production; Protein Isoforms; Proteins; Regulatory Pathway; Reporting; Research; Respiratory Center; Respiratory Disease; Respiratory System; Respiratory Tract Infections; Risk; Risk Factors; Role; Severities; System; TLR4 gene; TNF gene; Techniques; Testing; Tissues; Training; Universities; Viral; Virus Replication; airway surface liquid; blood glucose regulation; bronchial epithelium; career; cytokine; design; diabetic; experience; glucose metabolism; glucose transport; glucose uptake; in vivo; influenza infection; inhibitor; insight; non-diabetic; novel; response; therapeutic target; trafficking

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.

项目总结 虽然糖尿病已经达到流行水平，但流感等呼吸道感染长期以来一直居于高位 在全球死因名单上。糖尿病的定义是持续的高血糖状态，它导致 到多器官并发症。重要的是，高血糖是高血压的主要独立危险因素。 肺部感染，包括流感感染的发展和恶化。这种现象是 被认为是由于高血糖状态使患者容易摄入高于正常水平的葡萄糖而发生的 在呼吸道中的浓度，导致肺部感染的风险增加。虽然肺是一种主要的 利用葡萄糖的器官，肺中葡萄糖稳态的作用和调节研究很少。 请注意。因此，我们的长期目标是研究葡萄糖稳态的作用和改变 发生在呼吸道感染期间。从血液中摄取葡萄糖，限制葡萄糖的利用， 被称为葡萄糖转运体(GLUT)的一种特殊蛋白质家族严格调控。因为每一个细胞 表达这些葡萄糖，它们被认为是全身葡萄糖代谢的主要调节者，因此 是关键的药理作用靶点。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下。重要的是，我们最近证明了 在糖尿病期间，几种主要的和新的GLUT亚型在肺中的表达和活性发生了变化， 以及下游的胰岛素信号通路。我们进一步表明，糖尿病小鼠拥有更高的病毒 流感感染后支气管肺泡灌洗液中的滴度。因此，这个项目的总体目标是 是为了了解糖尿病期间肺内葡萄糖稳态的改变如何增强病毒复制 从而导致流感的发病机制。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会增加糖尿病动物肺部的流感感染； 糖尿病肺中胰岛素信号通路的改变可增强炎症反应 流感感染的严重程度。我们将在多个系统级别使用全面、集成的方法 最先进的技术和科布雷核心设施。一个跨学科的指导团队也将提供 在俄克拉何马州丰富的智力环境中具有密集合作研究经验的申请者 州立大学和俄克拉何马大学健康科学中心。从这项研究中获得的见解可能 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)确定 针对病毒流感感染的新的代谢治疗目标，这是该项目的一个关键成果。最后，通过 利用她在基础和临床科学方面的强大双重培训，该奖项旨在促进 申请人的发展，以实现其在呼吸道和传染病领域的职业目标。