Mechanisms of respiratory long-term facilitation

呼吸长期促进机制

基本信息

  • 批准号:
    7268831
  • 负责人:
  • 金额:
    $ 34.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-07-18 至 2009-06-30
  • 项目状态:
    已结题

项目摘要

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.
描述(由申请人提供):急性间歇性缺氧在呼吸的神经控制中激发一种独特形式的可塑性,即呼吸长期易化(LTF)。由此产生的可塑性是独特的,在这个意义上,一个相等的累积持续时间的持续缺氧不会引起相同的潜在机制。我们建议调查的细胞机制引起的膈神经活动(pLTF)在体内的LTF,并确定一些机制,区分持续性和间歇性缺氧。我们的工作模型是间歇性(但不是持续性)缺氧增加膈运动神经元内脑源性神经营养因子(BDNF)的合成。我们认为,脑源性神经营养因子激活膈运动神经元内的细胞外调节激酶(ERK 1/2),即MAP激酶家族的成员。ERK 1/2随后加强脑干运动前神经元和膈神经元之间的突触,从而建立pLTF。我们认为,持续缺氧是独特的,因为它也激活蛋白磷酸酶,停止导致BDNF合成增加的机制。因此,在间歇性但非持续性缺氧后观察到pLTF,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检验假设:1)间歇性(但非持续性)缺氧增加呼吸运动神经元附近的BDNF合成:2)膈运动神经元内BDNF合成增加是pLTF所必需的:3)间歇性缺氧后ERK 1/2 MAP激酶激活增加是pLTF所必需的; 4)持续性(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合成增加、ERK 1/2激活和pLTF增加的机制。这个建议的优势是多学科的方法,包括应用现代分子生物学技术,如RNA干扰,对呼吸神经可塑性在体内的理解。彻底了解导致呼吸可塑性的机制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、Rhett综合征和婴儿猝死综合征)的新治疗方法提供理论基础。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Gordon S. Mitchell其他文献

Enhanced phrenic motor neuron BDNF expression elicited by daily acute intermittent hypoxia is undermined in rats with chronic cervical spinal cord injury
  • DOI:
    10.1016/j.resp.2024.104369
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Aaron A. Jones;Jose R. Oberto;Marissa C. Ciesla;Yasin B. Seven;Latoya L. Allen;Elisa J. Gonzalez-Rothi;Gordon S. Mitchell
  • 通讯作者:
    Gordon S. Mitchell
Microglia regulate motor neuron plasticity via reciprocal fractalkine/adenosine signaling
小胶质细胞通过相互的分形蛋白/腺苷信号传导调节运动神经元可塑性
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Alexendria B. Marciante;Arash Tadjalli;Kayla A. Burrowes;J. Oberto;Edward K. Luca;Y. Seven;Maria Nikodemova;Jyoti J Watters;Tracy L. Baker;Gordon S. Mitchell
  • 通讯作者:
    Gordon S. Mitchell
Microglia regulate motor neuron plasticity via reciprocal fractalkine and adenosine signaling
小胶质细胞通过相互的 fractalkine 和腺苷信号调节运动神经元可塑性
  • DOI:
    10.1038/s41467-024-54619-x
  • 发表时间:
    2024-11-28
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Alexandria B. Marciante;Arash Tadjalli;Maria Nikodemova;Kayla A. Burrowes;Jose Oberto;Edward K. Luca;Yasin B. Seven;Jyoti J. Watters;Tracy L. Baker;Gordon S. Mitchell
  • 通讯作者:
    Gordon S. Mitchell
Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury
  • DOI:
    10.1016/j.expneurol.2024.115054
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Mehdi Ahmadian;Erin Erskine;Liisa Wainman;Oliver H. Wearing;Jennifer S. Duffy;Liam C. Stewart;Ryan L. Hoiland;Alissa Taki;Raphael R. Perim;Gordon S. Mitchell;Jonathan P. Little;Patrick J. Mueller;Glen E. Foster;Christopher R. West
  • 通讯作者:
    Christopher R. West
Concept Mapping in Pulmonary Physiology Using Pathfinder Scaling
使用 Pathfinder Scaling 进行肺生理学概念图绘制
  • DOI:
    10.1023/b:ahse.0000038299.79574.e8
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    4
  • 作者:
    W. McGaghie;D. McCrimmon;Gordon S. Mitchell;Jason A. Thompson
  • 通讯作者:
    Jason A. Thompson

Gordon S. Mitchell的其他文献

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{{ truncateString('Gordon S. Mitchell', 18)}}的其他基金

Microglial regulation of intermittent hypoxia induced phrenic motor plasticity
小胶质细胞对间歇性缺氧诱导的膈运动可塑性的调节
  • 批准号:
    10323659
  • 财政年份:
    2020
  • 资助金额:
    $ 34.49万
  • 项目类别:
Microglial regulation of intermittent hypoxia induced phrenic motor plasticity
小胶质细胞对间歇性缺氧诱导的膈运动可塑性的调节
  • 批准号:
    10078632
  • 财政年份:
    2020
  • 资助金额:
    $ 34.49万
  • 项目类别:
Microglial regulation of intermittent hypoxia induced phrenic motor plasticity
小胶质细胞对间歇性缺氧诱导的膈运动可塑性的调节
  • 批准号:
    10545056
  • 财政年份:
    2020
  • 资助金额:
    $ 34.49万
  • 项目类别:
Optimizing respiratory plasticity with chronic cervical SCI
优化慢性颈椎 SCI 的呼吸可塑性
  • 批准号:
    10439443
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:
Optimizing respiratory plasticity with chronic cervical SCI
优化慢性颈椎 SCI 的呼吸可塑性
  • 批准号:
    9906267
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:
Optimizing respiratory plasticity with chronic cervical SCI
优化慢性颈椎 SCI 的呼吸可塑性
  • 批准号:
    9763802
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:
Diversity Supplement for Ashley Ross Optimizing respiratory plasticity with chronic cervical SCI
Ashley Ross 的多样性补充剂优化慢性颈椎 SCI 的呼吸可塑性
  • 批准号:
    10077019
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:
Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity
间歇性缺氧引起的呼吸运动可塑性的调节
  • 批准号:
    10458511
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:
Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity
间歇性缺氧引起的呼吸运动可塑性的调节
  • 批准号:
    10213129
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:
Regulation of Intermittent Hypoxia-Induced Respiratory Motor Plasticity
间歇性缺氧引起的呼吸运动可塑性的调节
  • 批准号:
    9980491
  • 财政年份:
    2019
  • 资助金额:
    $ 34.49万
  • 项目类别:

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