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（由申请人提供）：可塑性和化塑性是控制呼吸的神经系统的标志特征。呼吸可塑性是呼吸的持续变化。 短暂刺激后的控制是表达可塑性（可塑性）的能力的变化，一种经过充分研究的呼吸可塑性模型是膈长期促进（pLTF），即暴露于中度急性刺激后膈运动输出的持续增加。间歇性缺氧（AIH）。反复急性间歇性缺氧（rAIH）。 慢性间歇性缺氧 (CIH) 会增强 pLTF，表明多种细胞机制会产生表型相似的持久膈运动易化 (pMF)，包括所谓的 pMF 的“Q”和“S”途径。这些途径以启动可塑性的 G 蛋白命名，例如，中度 AIH 诱导的 pLTF 需要 Gq 偶联的 5-HT2 受体激活、蛋白激酶 C。 (PKC) 活性、脑源性神经营养因子 (BDNF) 的新合成和通过 TrkB 和 ERK MAP 激酶离线的下游信号传导、Gs 偶联 5-HT7 受体的刺激激活 cAMP，诱导未成熟的 TrkB 亚型和下游蛋白激酶的新合成。 B/Akt 激活通常情况下，Q 和 S 途径通过相互（串扰）抑制相互作用，因此，在正常大鼠中，pLTF 的主导 Q 途径受到限制。亚阈值 S 途径激活（例如通过 5-HT7 受体激活）指导该建议的基本假设是，rAIH 预处理通过减少 S 和 Q 途径与 pMF 之间的串扰抑制来引发 pLTF 化塑性，从而增强中度 AIH 后的 pLTF。因此，我们预测 rAIH 增强的 pLTF（即化塑性）是由 5-HT2 和 5-HT7 受体的独立贡献引起的。从生物学角度来看，这项研究具有重要意义，因为它增进了我们对引起呼吸运动可塑性和后可塑性的基本机制的理解。从临床角度来看，rAIH 在损害呼吸和运动能力的衰弱临床疾病方面具有相当大的治疗潜力。非呼吸运动功能。