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 颈脊髓损伤 (cSCI) 破坏脊髓呼吸运动神经元的神经通路，导致 呼吸系统受损，甚至死亡。迫切需要新的治疗策略来改善呼吸 cSCI后的能力。由于大多数 cSCI 都是不完整的，因此可以通过利用来诱导有意义的功能恢复 神经可塑性的内在能力，加强通向呼吸运动神经元的神经通路。 重复性急性间歇性缺氧（rAIH）是一种简单、安全、有效的诱导呼吸运动的手段 可塑性并改善急性 cSCI 啮齿动物模型的呼吸能力。不幸的是，中度 rAIH 较少 对慢性 cSCI 有效。因此，与慢性（非急性）cSCI 相关的未知因素会破坏 rAIH 功效。候选者包括腺苷依赖性可塑性竞争机制的串扰抑制， 持续的神经炎症和年龄依赖性的性别二态性。在这个项目中，我们的基本目标 是：1）了解限制AIH引起的膈运动可塑性的因素； 2）运用这种理解 开发完善的 rAIH 方案，优化慢性 cSCI 的治疗效果。 AIH 引发多种不同的膈运动促进 (pMF) 机制，包括：1) 血清素依赖性 由颈动脉化学感受器激活启动的 Q 通路； 2) 腺苷依赖性 S 途径由 膈运动核局部缺氧。尽管如果单独激活每个途径都具有治疗潜力， 共激活导致通路竞争甚至 pMF 取消。我们假设慢性 cSCI 变化 Q&S 通路激活的平衡，破坏了 rAIH 的治疗效果。尽量减少脊柱 通过缩短 AIH 缺氧发作，缺氧和腺苷积累有望改善功能 通过消除腺苷对可塑性的限制来获得结果。由于炎症会破坏血清素（而不是 腺苷）依赖性 pMF，我们还将检验抗炎药物提高 rAIH 疗效的假设 患有慢性 cSCI。最后，由于 AIH 诱导的膈运动可塑性表现出深刻的年龄依赖性性行为 为了观察二态性，我们将比较 rAIH 在中年雄性和雌性大鼠中的疗效。通过使用两个已建立的模型 慢性（> 8 周）cSCI（C2 半截断和 C4 脊髓挫伤）的研究，我们预计会有更可靠的结论 因为每种模型都有独特的优点/局限性。提出了五个目标来检验以下假设：1) cSCI 降低脊髓 PO2，增加腺苷对 pMF 的限制； 2) 缺氧时间较短的AIH 减少组织缺氧和腺苷积累，优化 pMF； 3) 在雄性大鼠中，优化后的 rAIH 有所改善 呼吸能力超过“传统”rAIH； 4）抗炎药物增强rAIH疗效；和 5) 与雄性大鼠相比，优化的 rAIH 可以更好地改善中年雌性大鼠的呼吸能力。每个目标都得到支持 通过令人兴奋的初步数据证明可行性和概念证明。通过优化重复性 AIH- 诱导可塑性以提高呼吸能力，我们获得新的机制见解并更接近 针对因慢性 cSCI 导致呼吸受损的人类进行的综合临床试验。

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

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