Optimizing respiratory plasticity with chronic cervical SCI

优化慢性颈椎 SCI 的呼吸可塑性

• 批准号: 10439443
• 负责人: Gordon S. Mitchell
• 金额: $ 70.26万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10439443
• 关键词: Acute; Adenosine; Age; Anti-Inflammatory Agents; Basic Science; Brain Stem; Breathing; Cell Nucleus; Cervical; Cervical spinal cord injury; Cessation of life; Chemoreceptors; Chronic; Clinical; Clinical Trials; Contusions; Data; Disease; Educational workshop; Equilibrium; Exhibits; Exposure to; Female; Foundations; Funding; Goals; Human; Hypoxia; Impairment; Inflammation; Injury; Investigation; Limb structure; Maps; Modality; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Movement; Neural Pathways; Neuromuscular Diseases; Neuronal Plasticity; Neurons; Pathway interactions; Persons; Pharmaceutical Preparations; Protocols documentation; Rattus; Receptor Activation; Recommendation; Recording of previous events; Recovery of Function; Reporting; Rodent Model; Serotonin; Site; Spinal; Spinal Injuries; Spinal cord injury; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Walking; age related; base; clinical application; clinical translation; experimental study; extracellular; functional outcomes; improved; insight; male; middle age; mortality; motor function recovery; motor impairment; neuroinflammation; respiratory; sexual dimorphism; treatment strategy; young adult

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

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。

• DOI: 10.1152/japplphysiol.00486.2020
• 发表时间: 2020
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Welch,JosephF;Argento,PatrickJ;Mitchell,GordonS;Fox,EmilyJ
• 通讯作者: Fox,EmilyJ

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: Exercise and sport sciences reviews
• 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: Experimental neurology
• 影响因子: 5.3
• 作者: Perim RR;Gonzalez-Rothi EJ;Mitchell GS
• 通讯作者: Mitchell GS