Generation of Respiratory Rhythm

呼吸节律的产生

• 批准号: 7316130
• 负责人: JACK L FELDMAN
• 金额: $ 42.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316130
• 关键词: Acute; Address; Adult; Affect; Aging; Apnea; Behavior; Bilateral; Birth; Blood; Blood gas; Brain Stem; Breathing; Cell Nucleus; Central Alveolar Hypoventilation Syndrome; Central Sleep Apnea; Cessation of life; Cholinergic Agents; Complex; Condition; Coupled; Data; Development; Disease; Employee Strikes; Exercise; Failure; Figs - dietary; Functional disorder; Gases; Generations; Genus Capra; Goat; Grant; Health; Homeostasis; Human; Hypercapnic respiratory failure; Investigation; Label; Laboratories; Lesion; Mammals; Metabolism; Modeling; Motor Activity; Motor output; Mus; Mutant Strains Mice; Names; Neurons; Opioid; Outcome; Pathology; Pattern; Peptides; Periodicity; Pharmaceutical Preparations; Phenotype; Play; Pregnancy; Prematurity of fetus; Primates; Rattus; Research Personnel; Respiration; Rest; Rett Syndrome; Rodent; Role; Serotonin; Severities; Site; Sleep; Sleep Apnea Syndromes; Substance P Receptor; Sudden infant death syndrome; Syndrome; Temperature; Testing; United States National Institutes of Health; Vertebrates; Wakefulness; Week; Work; awake; base; cholinergic; clinically relevant; design; in vivo; neuroregulation; neurotransmission; noradrenergic; novel; prevent; programs; research study; respiratory

DESCRIPTION (provided by applicant): Breathing is a remarkable behavior that regulates gas exchange to support metabolism and regulate blood pH. Failure to breathe properly in humans suffering from disorders such as sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, Rett Syndrome, central alveolar hypoventilation, and perhaps sudden infant death syndrome, leads to serious adverse health consequences, even death. If these pathologies are to be understood, the site(s) and mechanisms of respiratory rhythmogenesis must be revealed. Our laboratory, through support of this and related NIH grants, have contributed in important ways to our current understanding of the control of breathing. We made two novel discoveries in the previous grant period: 1. Partial lesions of the preBotzinger Complex (preBotC) in adult rats causes sleep disordered breathing. We will exploit this model of central sleep apnea to address an important question of considerable clinical relevance: What can be done to reduce the severity of central sleep apnea? Can drugs affecting serotonin, noradrenergic, cholinergic or specific peptide neurotransmission affect central sleep apneas when directly applied to the preBotC? If so, this will provide important information about possible causes of central sleep apnea and of the state-dependent role of the preBotC in generation of breathing pattern. 2. Respiratory rhythm generation appears to involve two distinct anatomically separated oscillators: the preBotC and the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). We will look at mice (Krox20) with genetically-induced brainstem developmental anomalies that affect the RTN/pFRG. If our hypotheses are correct, we should see profound changes in expiratory-related activity. A complementary approach will be to record single neuron activity in the RTN/pFRG of rats. We predict we will observe rhythmically active RTN/pFRG when there is active expiratory motor output. These experiments, regardless of outcome, will help us to better understand RTN/pFRG function in normal and pathological states and under different experimental conditions and its interactions with the preBotC. The investigation and testing of the novel hypotheses arising from our recent discoveries should have fundamental impact on our understanding of breathing in humans in health and disease

描述（由申请人提供）：呼吸是一种调节气体交换以支持新陈代谢和调节血液 pH 值的非凡行为。患有睡眠呼吸暂停、早产儿呼吸暂停、先天性中枢性通气不足综合征、雷特综合征、中枢性肺泡通气不足以及婴儿猝死综合征等疾病的人类如果无法正常呼吸，会导致严重的不良健康后果，甚至死亡。如果要理解这些病理学，就必须揭示呼吸节律发生的部位和机制。我们的实验室通过这项资助和相关的 NIH 拨款的支持，为我们目前对呼吸控制的理解做出了重要贡献。我们在上一个资助期内取得了两项新发现： 1. 成年大鼠前博辛格复合体（preBotC）的部分损伤导致睡眠呼吸障碍。我们将利用这种中枢性睡眠呼吸暂停模型来解决一个具有相当临床意义的重要问题：可以采取哪些措施来减轻中枢性睡眠呼吸暂停的严重程度？当直接应用于 preBotC 时，影响血清素、去甲肾上腺素能、胆碱能或特定肽神经传递的药物是否会影响中枢性睡眠呼吸暂停？如果是这样，这将提供有关中枢性睡眠呼吸暂停的可能原因以及 preBotC 在呼吸模式生成中的状态依赖性作用的重要信息。 2. 呼吸节律的产生似乎涉及两个不同的解剖学上分离的振荡器：preBotC 和后梯形核/面旁呼吸组 (RTN/pFRG)。我们将研究具有影响 RTN/pFRG 的遗传性脑干发育异常的小鼠 (Krox20)。如果我们的假设是正确的，我们应该会看到与呼气相关的活动发生深刻的变化。一种补充方法是记录大鼠 RTN/pFRG 中的单个神经元活动。我们预测，当存在主动呼气运动输出时，我们将观察到有节奏的活跃 RTN/pFRG。这些实验，无论结果如何，都将帮助我们更好地了解正常和病理状态下以及不同实验条件下的 RTN/pFRG 功能及其与 preBotC 的相互作用。对我们最近发现的新假设的调查和测试应该对我们对健康和疾病中人类呼吸的理解产生根本性影响