Optimizing respiratory plasticity with chronic cervical SCI

优化慢性颈椎 SCI 的呼吸可塑性

基本信息

  • 批准号:
    10439443
  • 负责人:
  • 金额:
    $ 70.26万
  • 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:
    2019-04-04 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Cervical spinal cord injury (cSCI) disrupts neural pathways to spinal respiratory motor neurons, causing respiratory impairment and even death. New treatment strategies are desperately needed to improve breathing ability after cSCI. Since most cSCI are incomplete, meaningful functional recovery can be induced by harnessing the intrinsic capacity for neuroplasticity, strengthening spared neural pathways to respiratory motor neurons. Repetitive acute intermittent hypoxia (rAIH) is a simple, safe and effective means to induce respiratory motor plasticity and improve breathing ability in rodent models of acute cSCI. Unfortunately, moderate rAIH is less effective with chronic cSCI. Thus, unknown factors associated with chronic (not acute) cSCI undermine rAIH efficacy. Candidates include cross-talk inhibition from competing mechanisms of adenosine-dependent plasticity, persistent neuroinflammation and age-dependent sexual dimorphisms. In this project, our fundamental goals are: 1) to understand factors limiting AIH-induced phrenic motor plasticity; and 2) use that understanding to develop refined rAIH protocols that optimize therapeutic efficacy with chronic cSCI. AIH elicits multiple distinct mechanisms of phrenic motor facilitation (pMF), including: 1) serotonin-dependent Q pathway initiated by carotid chemoreceptor activation; and 2) adenosine-dependent S pathway initiated by local hypoxia in the phrenic motor nucleus. Although each pathway has therapeutic potential if activated alone, co-activation leads to pathway competition and even pMF cancellation. We hypothesize that chronic cSCI shifts the balance towards equal Q & S pathway activation, undermining rAIH therapeutic efficacy. Minimizing spinal hypoxia and adenosine accumulation by shortening AIH hypoxic episodes is predicted to improve functional outcomes by removing the adenosine constraint to plasticity. Since inflammation undermines serotonin (not adenosine)-dependent pMF, we will also test the hypothesis that anti-inflammatory drugs improve rAIH efficacy with chronic cSCI. Finally, since AIH-induced phrenic motor plasticity exhibits profound age-dependent sexual dimorphisms, we will compare rAIH efficacy in middle-aged male vs female rats. By using two established models of chronic (> 8 weeks) cSCI (C2 hemisection and C4 spinal contusion), we anticipate more robust conclusions since each model has unique advantages/limitations. Five aims are proposed to test the hypotheses that: 1) cSCI decreases spinal PO2, increasing the adenosine constraint to pMF; 2) AIH with shorter hypoxic episodes lessens tissue hypoxia and adenosine accumulation, optimizing pMF; 3) in male rats, optimized rAIH improves breathing capacity more than “conventional” rAIH; 4) anti-inflammatory drugs enhance rAIH efficacy; and 5) optimized rAIH improves breathing capacity more in middle-aged female versus male rats. Each aim is supported by exciting preliminary data demonstrating feasibility and proof of concept. By optimizing repetitive AIH- induced plasticity to improve breathing ability, we gain new mechanistic insights and move closer to comprehensive clinical trials in humans suffering from impaired breathing due to chronic cSCI.
摘要

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Reliability of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation.
经颅磁刺激引起的膈肌运动诱发电位的可靠性。
Synergy between Acute Intermittent Hypoxia and Task-Specific Training.
急性间歇性缺氧与特定任务训练之间的协同作用。
  • DOI:
    10.1249/jes.0000000000000222
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    5.7
  • 作者:
    Welch,JosephF;Sutor,TommyW;Vose,AliciaK;Perim,RaphaelR;Fox,EmilyJ;Mitchell,GordonS
  • 通讯作者:
    Mitchell,GordonS
Cervical spinal injury compromises caudal spinal tissue oxygenation and undermines acute intermittent hypoxia-induced phrenic long-term facilitation.
  • DOI:
    10.1016/j.expneurol.2021.113726
  • 发表时间:
    2021-08
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Perim RR;Gonzalez-Rothi EJ;Mitchell GS
  • 通讯作者:
    Mitchell GS
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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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 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:
    $ 70.26万
  • 项目类别:

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