Neural Plasticity During Acclimatization to Hypoxia

适应缺氧过程中的神经可塑性

• 批准号: 8700460
• 负责人: Frank L. Powell
• 金额: $ 37.98万
• 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 2016-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700460
• 关键词: Acclimatization; Acute; Address; Affinity; American Society of Hematology; Animal Model; Animals; Apnea; Blood; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Carbon Dioxide; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Complex; Conscious; Dependovirus; Disease; Experimental Designs; Gene Deletion; Genetic; Genetic Engineering; Glutamate Receptor; Glutamates; Hypoxemia; Hypoxia; In Vitro; Inflammation; Lung; Lung diseases; Measures; Mediating; Mitochondria; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Mus; N-Methyl-D-Aspartate Receptors; NADPH Oxidase; Neuraxis; Neuronal Plasticity; Neurons; Oxygen; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Population; Production; Protein Kinase; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Pulmonary Emphysema; Pulmonology; Purinergic P1 Receptors; Rattus; Reactive Oxygen Species; Receptor Activation; Receptor Protein-Tyrosine Kinases; Reflex control; Reporting; Research; Role; Signal Transduction; Sleep Apnea Syndromes; Source; Spinal Cord; Testing; Time; Transgenic Mice; VEGFA gene; design; in vivo imaging; mouse model; neuromechanism; neuroregulation; neurotransmission; novel; receptor; receptor coupling; recombinase; research study; respiratory; serotonin receptor; therapeutic target

DESCRIPTION (provided by applicant): The objective of this project is to determine the cellular signals for plasticity in central nervous system components of ventilatory chemoreflexes during Chronic Sustained Hypoxia (CSH). The significance of this research is that it addresses a fundamental but unanswered question in pulmonary medicine: What are the neural mechanisms that increase ventilatory drive and enhance the reflex control of arterial O2 and CO2 during chronic hypoxemia from pulmonary disease? More specifically, we will test the hypothesis that some of the same molecular signals and cellular mechanisms described by others to explain Long Term Facilitation (LTF) with intermittent hypoxia (IH) also contribute to plasticity in ventilatory chemoreflexes during CSH. There has been tremendous progress on mechanisms of LTF recently, which allows us to efficiently test evaluate the model in CSH. Comparing and contrasting plasticity in CSH and IH is significant by allowing us to systematically evaluate potential therapeutic targets for the most important causes of chronic hypoxemia, namely COPD causing CSH and sleep disordered breathing causing IH. First we will establish that the molecular signals for enhanced glutamatergic neurotransmission reported for phrenic LTF in anesthetized rats occur with ventilatory LTF after IH in conscious mice. Then we will measure those molecular signals in mice after CSH and use pharmacology and conditional gene deletion to test their physiological significance for ventilatory acclimatization to CSH. Drugs or Cre-recombinase expressed by adeno-associated virus will be microinjected intrathecally to the spinal cord or stereotaxically in the brainstem of wildtype or transgenic mice to manipulate putative signals for plasticity in different populations of respiratory neurons. Experiments are designed to compare and contrast plasticity with IH vs. CSH. For example, we hypothesize that TrkB phosphorylation is a signal for plasticity in both IH and CSH but BDNF is only a signal in IH. Also, we hypothesize that increases in Reactive Oxygen Species (ROS) with both IH and CSH are an important signal for plasticity and we will measure the time course of ROS changes with different patterns of hypoxia and alter them to test physiological significance. Finally, we will test the hypothesis that CSH causes similar molecular signals for plasticity in a transgenic mouse model of emphysema (conditional deletion of the vascular endothelial growth factor gene in the lung). This is our first step towards addressing the important question of whether the neural plasticity studied in healthy animals acclimatized to environmental hypoxia occurs in diseases with chronic hypoxemia, or if chronic lung disease also involves abnormal plasticity.

描述（由申请人提供）：本项目的目的是确定慢性持续性缺氧（CSH）期间中枢神经系统成分中诱导性化学反射可塑性的细胞信号。这项研究的意义在于它解决了肺医学中一个基本但未回答的问题：在肺部疾病引起的慢性低氧血症期间，增加呼吸驱动并增强动脉O2和CO2反射控制的神经机制是什么？更具体地说，我们将测试的假设，即一些相同的分子信号和细胞机制所描述的其他解释长期促进（LTF）与间歇性缺氧（IH）也有助于可塑性在CSH期间的化学反射。近年来对LTF机制的研究取得了巨大的进展，这使得我们能够在CSH中有效地测试和评估该模型。通过比较和对比CSH和IH的可塑性，我们可以系统地评估慢性低氧血症最重要原因的潜在治疗靶点，即导致CSH的COPD和导致IH的睡眠呼吸障碍。首先，我们将确定，在清醒小鼠IH后，麻醉大鼠膈LTF中报告的增强的多巴胺能神经传递的分子信号发生在诱导性LTF中。然后，我们将在CSH后小鼠中测量这些分子信号，并使用药理学和条件基因删除来测试它们对CSH的解释性习服的生理意义。将由腺相关病毒表达的药物或Cre重组酶鞘内显微注射到野生型或转基因小鼠的脊髓或脑干中，以操纵不同呼吸神经元群体中可塑性的推定信号。实验的目的是比较和对比与IH与CSH的可塑性。例如，我们假设TrkB磷酸化是IH和CSH中可塑性的信号，但BDNF仅是IH中的信号。此外，我们假设IH和CSH中活性氧（ROS）的增加是可塑性的重要信号，我们将测量不同缺氧模式下ROS变化的时间过程，并改变它们以测试生理意义。最后，我们将测试的假设，CSH导致类似的分子信号的可塑性在转基因小鼠模型肺气肿（条件删除的血管内皮生长因子基因在肺）。这是我们解决以下重要问题的第一步：在适应环境缺氧的健康动物中研究的神经可塑性是否发生在慢性低氧血症疾病中，或者慢性肺病是否也涉及异常可塑性。