Mechanisms of respiratory long-term facilitation

描述（由申请人提供）：急性间歇性缺氧在呼吸的神经控制中引起独特形式的可塑性，呼吸长期促进（LTF）。由此产生的可塑性是独特的，因为相同的持续缺氧的累积时间不会引起相同的潜在机制。我们建议研究在体内膈神经活动（pLTF）中引起LTF的细胞机制，并确定区分持续缺氧和间歇性缺氧的一些机制。我们的工作模型是间歇性（但不是持续的）缺氧增加了膈运动神经元内脑源性神经营养因子（BDNF）的合成。我们提出BDNF激活膈运动神经元内MAP激酶家族成员细胞外调节激酶（ERK 1/2）。ERK 1/2随后增强脑干前运动神经元和膈神经元之间的突触，从而建立pLTF。我们认为，持续缺氧的独特之处在于，它也激活了蛋白磷酸酶，从而阻止了导致BDNF合成增加的机制。因此，pLTF是在间歇性而非持续性缺氧后观察到的，主要是通过磷酸酶活性的差异调节。我们将追求四个具体目标来验证以下假设：1)间歇性（但不是持续）缺氧会增加呼吸运动神经元附近BDNF的合成；2)膈运动神经元内BDNF合成增加是pLTF的必要条件；3)间歇性缺氧后ERK 1/2 MAP激酶激活增加是pLTF的必要条件；4)持续（但不是间歇性）缺氧激活膈运动神经元内的蛋白磷酸酶，并停止导致BDNF合成，ERK 1/2激活和pLTF增加的机制。该建议的一个优势是多学科方法，包括RNA干扰等现代分子生物学技术的应用，以了解体内呼吸神经可塑性。对呼吸可塑性机制的深入了解可能为治疗破坏性呼吸控制障碍（如阻塞性睡眠呼吸暂停、脊髓损伤后呼吸功能不全、瑞德综合征和婴儿猝死综合征）提供新的治疗方法。

DESCRIPTION (provided by applicant): Acute intermittent hypoxia elicits a unique form of plasticity in the neural control of breathing, respiratory long-term facilitation (LTF). The resulting plasticity is unique in the sense that an equal cumulative duration of sustained hypoxia does not elicit the same underlying mechanisms. We propose to investigate cellular mechanisms giving rise to LTF in phrenic nerve activity (pLTF) in vivo, and to determine some of the mechanisms that distinguish sustained and intermittent hypoxia. Our working model is that intermittent (but not sustained) hypoxia increases synthesis of brain-derived neurotrophic factor (BDNF) within phrenic motoneurons. We propose that BDNF activates extracellular regulated kinases (ERK 1/2), members of the MAP kinase family, within phrenic motoneurons. ERK 1/2 subsequently strengthens the synapse between brainstem premotor neurons and phrenic neurons, thereby establishing pLTF. We suggest that sustained hypoxia is unique in that it also activates protein phosphatases, which halt the mechanisms leading to increased BDNF synthesis. Thus, pLTF is observed following intermittent, but not sustained, hypoxia, largely through the differential regulation of phosphatase activity. We will pursue four specific aims to test the hypotheses that: 1) Intermittent (but not sustained) hypoxia increases BDNF synthesis near respiratory motoneurons; 2) Increased BDNF synthesis within phrenic motoneurons is necessary for pLTF; 3) Increased ERK 1/2 MAP kinase activation following intermittent hypoxia is necessary for pLTF; and 4) Sustained (but not intermittent) hypoxia activates protein phosphatases within phrenic motoneurons and halts the mechanisms leading to increased BDNF synthesis, ERK 1/2 activation and pLTF. A strength of this proposal is the multidisciplinary approach, including the application of modern molecular biological techniques such as RNA interference, towards an understanding of respiratory neuroplasticity in vivo. A thorough understanding of mechanisms leading to respiratory plasticity may provide the rationale for new therapeutic approaches to the treatment of devastating respiratory control disorders such as obstructive sleep apnea, respiratory insufficiency following spinal cord injury, Rhett Syndrome and Sudden Infant Death Syndrome.