Neural Plasticity During Acclimatization to Hypoxia

适应缺氧过程中的神经可塑性

• 批准号: 9292348
• 负责人: Frank L. Powell
• 金额: $ 39.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9292348
• 关键词: Acclimatization; Address; Affect; Altitude; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Bacterial Infections; Brain; Brain Stem; Breathing; Carotid Body; Cell Nucleus; Chemoreceptors; Chronic; Chronic Obstructive Airway Disease; Clinical; Combined Modality Therapy; Conscious; Data; Denervation; Dinoprostone; Disease Progression; Environmental air flow; Gene Deletion; Gene Expression; Grant; Human; Hypoxemia; Hypoxia; Hypoxia Inducible Factor; Ibuprofen; In Vitro; Individual; Individual Differences; Inflammation; Inflammatory; Interleukin-1 Receptors; Isomerism; Laboratories; Lung diseases; Measures; Mechanical ventilation; Methods; Microglia; Molecular; Neuraxis; Neuronal Plasticity; Neurons; Non-Steroidal Anti-Inflammatory Agents; Oxygen; PTGS2 gene; Pattern; Pharmaceutical Preparations; Production; Protein Isoforms; Pulmonology; Rattus; Reactive Oxygen Species; Reflex control; Research; Respiratory Center; Rodent; Rodent Model; Role; Sepsis; Signal Transduction; Testing; Time; Transcript; Transgenic Mice; Vascular Endothelial Growth Factors; Weaning; cytokine; experimental study; glial activation; inhibitor/antagonist; innovation; neuromechanism; public health relevance; receptor; response; transcription factor

 DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine the molecular signals for plasticity in central nervous system that change the reflex control of breathing during chronic hypoxia. This research is significant because it addresses a fundamental but unanswered question in pulmonary medicine: Do changes in the control of breathing occur with chronic hypoxemia from lung disease and, if so, are there individual differences and how do they affect the progression of disease? We have developed methods to study the basic problem at the molecular level in conscious behaving laboratory rodent models, and results from these experiments have produced hypotheses that we have been able to test in humans. Specifically, we have shown that the common anti-inflammatory drug ibuprofen blocks time dependent increases in ventilation and ventilatory sensitivity to oxygen during chronic hypoxia in rodents and in healthy humans. This poses exciting new questions about the role of inflammatory signals for healthy and normal plasticity in the chemoreflex control of breathing. For example, inflammation is necessary for ventilatory acclimatization to hypoxia, which is beneficial by increasing O2 supply when O2 availability is decreased for long periods of time, but inflammation with bacterial infection can decrease ventilation and O2 supply, which exacerbates conditions. Also, we have preliminary data showing the transcription factor hypoxia inducible factor-1α (HIF-1α) is necessary in brainstem respiratory centers for normal ventilatory acclimatization to hypoxia in transgenic mice. Here we propose to test the hypothesis that both inflammatory signals and HIF-1α are necessary for plasticity in the control of breathing with chronic sustained hypoxia. In three specific aims, we will test the hypotheses that chemoreflex plasticity with chronic hypoxia requires (1) activation of NF-κB and HIF-1α in brainstem respiratory centers, (2) carotid body chemoreceptor afferent activation of microglia followed by astroglia activation that sustains an inflammatory and HIF-1α response, and (3) other isoforms of HIF in the brainstem are not necessary because reactive oxygen species (ROS) are not changing there with chronic hypoxia, although HIF-2α can affect the stability of breathing. Answering such questions could be important for common clinical scenarios where hypoxia and inflammation occur together, for example in COPD exacerbations or weaning from mechanical ventilation after sepsis in the ICU.

 描述（由申请人提供）：该提案的总体目标是确定中枢神经系统可塑性的分子信号，这些信号改变慢性缺氧期间呼吸的反射控制。这项研究意义重大，因为它解决了肺部医学中一个基本但尚未解答的问题：呼吸控制的变化是否会因肺部疾病引起的慢性低氧血症而发生，如果是的话，是否存在个体差异以及它们如何影响疾病的进展？我们开发了在有意识行为的实验室啮齿动物模型中在分子水平上研究基本问题的方法，并且这些实验的结果产生了我们能够在人类身上进行测试的假设。具体来说，我们已经证明，在啮齿类动物和健康人类的慢性缺氧过程中，常见的抗炎药布洛芬可以阻止通气和通气对氧气的敏感性的时间依赖性增加。这提出了令人兴奋的新问题，即炎症信号在化学反射控制呼吸中对健康和正常可塑性的作用。例如，炎症对于通气适应缺氧是必要的，当氧气供应量长期减少时，增加氧气供应是有益的，但细菌感染引起的炎症会减少通气和氧气供应，从而加剧病情。此外，我们有初步数据表明转录因子缺氧诱导因子-1α（HIF-1α）对于脑干呼吸中枢正常通气是必需的 转基因小鼠对缺氧的适应。在这里，我们建议检验以下假设：炎症信号和 HIF-1α 对于控制慢性持续缺氧呼吸的可塑性是必需的。在三个具体目标中，我们将测试以下假设：慢性缺氧时的化学反射可塑性需要（1）脑干呼吸中枢中的 NF-κB 和 HIF-1α 激活，（2）小胶质细胞的颈动脉体化学感受器传入激活，随后星形胶质细胞激活以维持炎症和 HIF-1α 反应，以及（3）脑干中的其他 HIF 亚型不是必需的，因为 尽管 HIF-2α 会影响呼吸的稳定性，但活性氧 (ROS) 不会因慢性缺氧而发生变化。回答这些问题对于缺氧和炎症同时发生的常见临床情况可能很重要，例如在 ICU 中慢性阻塞性肺病 (COPD) 恶化或脓毒症后停止机械通气时。