Hypoxia: an activator of neuroimmunity

缺氧：神经免疫激活剂

• 批准号: 8212047
• 负责人: Gregory G Freund
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212047
• 关键词: Accidents; Acute; Address; Adipose tissue; Anti-Inflammatory Agents; Anti-inflammatory; Base of the Brain; Behavior; Behavior Therapy; Behavioral; Brain; Clinical; Critiques; Cytoskeletal Proteins; Data; Desire for food; Development; Disease; Effectiveness; Environment; Evaluation; Failure; Fatty acid glycerol esters; Financial compensation; Future; Goals; Grant; Health; Hippocampus (Brain); Hour; Human; Hypoxia; Immune system; Infection; Inflammatory; Interleukin-1; Interleukin-12; Kineret; Laboratories; Leptin; Libido; Link; Mediating; Microtubule-Associated Protein 2; Microtubules; Motor Activity; Mus; Neurons; Nitrogen; Obesity; Outcome; Oxygen; Phase; Physical environment; Play; Principal Investigator; Production; Protein Isoforms; Publications; Published Comment; Recovery; Research; Role; Running; Signal Pathway; Signal Transduction; Social Environment; Speed; Staining method; Stains; Stimulus; Subcutaneous Injections; System; Toll-like receptors; Up-Regulation; Vanadium; arm; cytokine; db/db mouse; experience; improved; innovation; insight; interest; leptin receptor; neocortical; neuronal growth; novel; prevent; programs; receptor; research study; response; social; subcutaneous

DESCRIPTION (provided by applicant): Sickness behavior has been defined classically as a coordinated set of nonspecific behavioral modifications including loss of appetite, libido, motor activity and interest in the physical and social environment that occur in response to infection. New research from our laboratory shows that acute hypoxia induces loss of social exploration in mice, demonstrating that non-infectious stimuli can activate the neuroimmune system and stimulate sickness behavior. Acute hypoxia occurs in many types of accidents and in a host of disease states, yet little is known about immunobehavioral activation and recovery from acute hypoxia. Our exciting new data demonstrate that acute hypoxia elicits loss of social exploration and rapid up-regulation of brain IL-12. Importantly, this acute hypoxia-induced sickness behavior is dramatically shortened in mice deficient in IL-1 receptor/Toll-like receptor superfamily signaling. In leptin receptor defective mice, we have shown that acute hypoxia-induced sickness is longer lasting and ameliorated by subcutaneous administration of IL-1 receptor antagonist (IL-1RA). Together, these data indicate that acute hypoxia triggers activation of the brain-based innate immune system. The objective of this application is to examine the hypothesis that acute hypoxia activates the IL-1 arm of the neuroimmune system causing sickness behavior during hypoxia recovery. The long-term goal of this project is to understand the mechanisms of immunobehavioral recovery from acute hypoxia and to develop strategies that prevent and/or speed recovery from the immunobehavioral consequences of acute hypoxia. In Objective #1, we will define the acute hypoxia-induced sickness behaviors experienced during hypoxia recovery and determine if they are mediated by the pro-inflammatory cytokine IL-12. In Objective #2, we will ascertain if leptin is essential to rapidly resolving loss of social exploration due to acute hypoxia and discover the impact of obesity on recovery from acute hypoxia-induced sickness behaviors. In Objective #3, we will use a pharmacologic approach featuring IL-1RA to speed recovery from acute hypoxia-induced sickness behaviors, determine the importance of the IL-1 decoy receptor (IL-1R2) to acute hypoxia recovery and ascertain if vanadium-dependent up-regulation of brain IL-1RA and/or IL- 1R2 can provide protection from acute hypoxia. These studies are needed to define new targets in order to alleviate suffering in those afflicted by acute hypoxia.

描述（由申请人提供）：疾病行为被经典地定义为一组协调的非特异性行为改变，包括食欲、性欲、运动活动以及对身体和社会环境的兴趣的丧失，这些都是对感染的反应。我们实验室的新研究表明，急性缺氧会导致小鼠丧失社交探索能力，这表明非感染性刺激可以激活神经免疫系统并刺激疾病行为。急性缺氧发生在许多类型的意外事故和许多疾病状态中，但对急性缺氧的免疫行为激活和恢复知之甚少。我们令人兴奋的新数据表明，急性缺氧导致社会探索能力丧失和脑IL-12的快速上调。重要的是，在缺乏IL-1受体/ toll样受体超家族信号的小鼠中，这种急性缺氧引起的疾病行为显着缩短。在瘦素受体缺陷的小鼠中，我们已经表明，通过皮下注射IL-1受体拮抗剂（IL-1RA），急性缺氧引起的疾病持续时间更长，并得到改善。综上所述，这些数据表明急性缺氧触发了基于大脑的先天免疫系统的激活。本应用的目的是检验急性缺氧激活神经免疫系统IL-1臂导致缺氧恢复期间疾病行为的假设。该项目的长期目标是了解急性缺氧后免疫行为恢复的机制，并制定预防和/或加速急性缺氧免疫行为恢复的策略。在目标#1中，我们将定义在缺氧恢复期间经历的急性缺氧引起的疾病行为，并确定它们是否由促炎细胞因子IL-12介导。在目标2中，我们将确定瘦素是否对快速解决急性缺氧导致的社会探索能力丧失至关重要，并发现肥胖对急性缺氧引起的疾病行为恢复的影响。在目标#3中，我们将使用以IL- 1ra为特征的药理学方法来加速急性缺氧引起的疾病行为的恢复，确定IL-1诱饵受体（IL-1R2）对急性缺氧恢复的重要性，并确定钒依赖性上调脑IL- 1ra和/或IL-1R2是否可以提供急性缺氧保护。这些研究需要确定新的目标，以减轻急性缺氧患者的痛苦。