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

基本信息

  • 批准号:
    10213129
  • 负责人:
  • 金额:
    $ 59.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-07-19 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Plasticity is a hallmark of the neural system controlling breathing. One extensively studied form of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic motor output after acute intermittent hypoxia (AIH). Multiple, distinct cellular mechanisms contribute to AIH-induced pLTF. Unfortunately, our understanding of how these mechanisms are regulated is limited. Two distinct mechanisms of AIH-induced phrenic motor facilitation (pMF) are known as the Q and S pathways. The Q pathway requires phrenic motor neuron 5-HT2 receptor activation, whereas the S pathway is initiated by phrenic motor neuron 5-HT7 receptors. Q and S pathway co-activation elicits powerful cross-talk inhibition; in fact, equal Q and S pathway activation cancels pMF expression. With moderate AIH (mAIH), the Q pathway dominates but is constrained by S pathway inhibition; S pathway inhibition releases this “brake,” doubling mAIH-induced pLTF. Repetitive AIH (rAIH) preconditioning enhances mAIH-induced pLTF through unknown mechanisms. This property is essential in our translational efforts to harness rAIH as a treatment to improve breathing in people with cervical spinal injury or neuromuscular disease. The fundamental goal of this proposal is to understand how these cumulative rAIH benefits arise. Our central hypothesis is that rAIH minimizes Q-S pathway cross-talk interactions, enabling both to contribute to AIH-induced phrenic motor plasticity. AIH-induced phrenic motor plasticity exhibits profound age-dependent sexual dimorphism. However, we know essentially nothing concerning how age and sex alter differentially affect pMF mechanisms, or their response to rAIH preconditioning. Thus, we will compare Q and S pathway interactions in young (3 month) and middle-aged (12 month) female vs male rats (when sexual dimorphisms are greatest). We will also investigate differential rAIH preconditioning effects on diaphragm LTF in unanesthetized young and middle-aged female vs male rats. Increased understanding of age and sex effects in normal rats will establish the “ground rules” for translation to clinical disorders that afflict men and women of different ages. We propose a working cellular model of rAIH-enhanced pLTF based on literature and exciting preliminary data. Based on this model, we propose four specific aims to test the hypotheses that rAIH preconditioning: 1) decreases Q and S pathway cross-talk inhibition, enabling contributions from both (Aim 1); and 2) strengthens the Q pathway to pMF by increasing the expression of key pathway molecules (Aim 2). Since AIH-induced pLTF exhibits profound age-dependent sexual dimorphisms, we will test the hypotheses that: 1) the Q and S pathways to pMF are differentially affected by age and the estrus cycle female rats (Aim 3); and 2) age and sex are key determinants of rAIH-enhanced diaphragm motor plasticity (Aim 4). These studies will greatly advance our understanding of rAIH-enhanced phrenic motor plasticity, and accelerate our ability to harness rAIH as a therapeutic modality to treat devastating clinical disorders that compromise breathing and threaten life itself.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
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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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 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:
    $ 59.4万
  • 项目类别:
Breathing Research and Therapeutics (BREATHE)
呼吸研究和治疗(BREATHE)
  • 批准号:
    9901627
  • 财政年份:
    2017
  • 资助金额:
    $ 59.4万
  • 项目类别:

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