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.

抽象的 宫颈脊髓损伤（CSCI）破坏了脊柱呼吸运动神经元的神经元途径 呼吸障碍甚至死亡。迫切需要新的治疗策略来改善呼吸 CSCI之后的能力。由于大多数CSCI都是不完整的，因此可以通过利用有意义的功能恢复 神经塑性的内在能力，增强了呼吸运动神经元的宽松神经病。 重复的急性急性间歇性缺氧（RAIH）是一种简单，安全有效的手段，可诱导呼吸运动 可塑性并提高急性CSCI啮齿动物模型的呼吸能力。不幸的是，中度raih少 慢性CSCI有效。那是与慢性（而不是急性）CSCI有关的未知因素破坏Raih 效率。候选人包括依赖腺苷依赖性可塑性机制的串扰抑制， 持续的神经炎症和年龄依赖性二态性。在这个项目中，我们的基本目标 是：1）了解限制AIH引起的phren型运动可塑性的因素； 2）使用这种理解 开发精致的RAIH方案，以优化慢性CSCI的治疗效率。 AIH引起了伪运动设施（PMF）的多种不同机制，包括：1）5-羟色胺依赖性 颈动脉化学感受器激活引发的Q途径； 2）由腺苷依赖性的途径 运动核中的局部缺氧。尽管每个途径单独激活，都具有治疗潜力 共同激活导致途径竞争，甚至取消PMF。我们假设慢性CSCI改变 朝相等的Q＆S途径激活的平衡，破坏了RAIH治疗效率。最小化脊柱 预测通过缩短AIH低氧发作来改善功能性，低氧和腺苷积累 通过去除腺苷对可塑性的约束来取得结果。由于炎症破坏了5-羟色胺（不是 腺苷依赖性PMF，我们还将检验以下假设：抗炎药提高了RAIH效率 与慢性CSCI。最后，由于AIH诱导的Phrenial运动可塑性表现出深远的年龄依赖性性 二态性，我们将比较中年男性与雌性大鼠的RaiH效率。通过使用两个既定模型 慢性（> 8周）CSCI（C2 Hemisection和C4脊柱挫伤），我们预期会有更健壮的结论 由于每个模型都有唯一的优势/限制。提出了五个目标来检验：1） CSCI降低了脊柱PO2，将腺苷的约束增加到PMF。 2）AIH较短的低氧发作 减少组织缺氧和腺苷的积累，优化的PMF； 3）在雄性大鼠中，优化的Raih改善 呼吸能力比“常规” Raih更重要； 4）抗炎药提高了RAIH效率； 5） 优化的RAIH可改善中年女性与雄性大鼠的呼吸能力。每个目标都得到支持 通过令人兴奋的初步数据证明了可行性和概念证明。通过优化重复的AIH- 诱导可塑性以提高呼吸能力，我们获得了新的机械见解，并靠近 慢性CSCI呼吸受损的人类的全面临床试验。

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

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

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