Repetitive acute intermittent hypoxia elicits respiratory metaplasticity

反复急性间歇性缺氧引起呼吸道化生

• 批准号: 8835755
• 负责人: Daryl Fields
• 金额: $ 3.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835755
• 关键词: Acute; Address; Biological; Brain-Derived Neurotrophic Factor; Breathing; Cervical; Chronic; Clinical; Complex; Coupled; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease; Exposure to; Extracellular Signal Regulated Kinases; GTP-Binding Proteins; Genetic; Goals; Human; Hypoxia; Individual; Mediating; Morbidity - disease rate; Motor; Motor Neuron Disease; Motor output; Names; Nerve Degeneration; Pathway interactions; Plastics; Protein Isoforms; Protein Kinase C; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Receptor Activation; Receptor Inhibition; Rehabilitation therapy; Research; Respiratory Insufficiency; Serotonin; Signal Transduction; Spinal; Spinal Injuries; Stimulus; Study models; System; Testing; Therapeutic; Ursidae Family; clinically significant; innovation; mortality; motor deficit; nervous system disorder; preconditioning; public health relevance; receptor; relating to nervous system; respiratory; serotonin 7 receptor; tool

 DESCRIPTION (provided by applicant): Plasticity and metaplasticity are hallmark features of the neural system controlling breathing. Respiratory plasticity is a persistent change in breathing control following transient stimuli. Metaplasticity is a change in the capacity to express plasticiy (plastic plasticity). One well-studied model of respiratory plasticity is phrenic long- term facilitation (pLTF), a persistent increase in phrenic motor output following exposure to moderate acute intermittent hypoxia (AIH). Preconditioning with repetitive acute intermittent hypoxia (rAIH) or chronic intermittent hypoxia (CIH) enhances pLTF, demonstrating a degree of respiratory metaplasticity. Multiple cellular mechanisms give rise to phenotypically similar long-lasting phrenic motor facilitation (pMF), including the so-called "Q" and "S" pathways to pMF. These pathways are named for the G proteins initiating plasticity. For example, moderate AIH-induced pLTF requires Gq-coupled 5-HT2 receptor activation, protein kinase C (PKC) activity, new synthesis of brain derived neurotrophic factor (BDNF) and downstream signaling via TrkB and ERK MAP kinases. Conversely, stimulation of Gs coupled 5-HT7 receptors activates cAMP, inducing new synthesis of an immature TrkB isoform and downstream protein kinase B/Akt activation. Normally, the Q and S pathways interact via mutual (cross-talk) inhibition. Thus, in normal rats, the dominant Q pathway to pLTF is constrained by sub-threshold S pathway activation (eg. by 5-HT7 receptor activation). The fundamental hypothesis guiding this proposal is that rAIH preconditioning elicits pLTF metaplasticity by reducing cross-talk inhibition between the S and Q pathways to pMF, thereby enhancing pLTF following moderate AIH by enabling independent contributions from both pathways. Thus, we predict that rAIH-enhanced pLTF (ie. metaplasticity) results from independent contributions from both 5-HT2 and 5-HT7 receptor activation. This research is significant from a biological perspective since it advances our understanding of basic mechanisms giving rise to respiratory motor plasticity and meta-plasticity. It is significant from a clinical perspective since rAIH has considerable therapeutic potential in debilitating clinical disorders that compromise respiratory and non-respiratory motor function.

 描述（由应用程序提供）：可塑性和化学性是控制呼吸的神经系统的标志性特征。呼吸可塑性是呼吸的持续变化 在短暂刺激之后进行控制。塑性性是表达生长良好的能力（塑性可塑性）的变化。一个良好的呼吸可塑性模型是长期的长期设施（PLTF），暴露于中度急性急性间歇性缺氧（AIH）后，发动机输出持续增加。重复急性急性间歇性缺氧（RAIH）的预处理 或慢性间歇性缺氧（CIH）增强了PLTF，表现出一定程度的呼吸质塑性。多种细胞机制产生了表观上相似的长期伪运动设施（PMF），包括所谓的“ Q”和“ S”途径到达PMF。这些途径以G蛋白启动可塑性命名。例如，中等AIH诱导的PLTF需要GQ耦合5-HT2受体激活，蛋白激酶C（PKC）活性，脑衍生的神经营养因子（BDNF）的新合成以及通过TRKB和ERK MAP激酶通过TRKB和ERK MAP激酶的下游信号传导。相反，GS耦合5-HT7受体的刺激激活了CAMP，引起了未成熟的TRKB同工型和下游蛋白激酶B/AKT激活的新合成。通常，Q和S途径通过相互抑制（通过跨对）相互作用。在正常大鼠中，PLTF的主要Q途径受到亚阈值的途径激活的约束（例如，通过5-HT7受体激活）。指导这一建议的基本假设是，RAIH预处理通过减少S和Q途径之间的跨对抑制作用到PMF，从而引起PLTF的质感性，从而通过从两种途径中实现独立的贡献来增强PLTF。这是我们预测，RAIH增强的PLTF（即化学性）是由5-HT2和5-HT7受体激活的独立贡献引起的。从生物学的角度来看，这项研究很重要，因为它可以提高我们对基本机制的理解，从而引起呼吸运动可塑性和元塑性。从临床角度来看，这很重要，因为Raih考虑了损害呼吸和非呼吸运动功能的临床疾病的治疗潜力。