Harnessing tongue exercise to enhance neuroplasticity and preserve upper airway function in a novel model of hypoglossal motor neuron degeneration
在舌下运动神经元变性的新型模型中利用舌头运动增强神经可塑性并保留上呼吸道功能
基本信息
- 批准号:10673603
- 负责人:
- 金额:$ 50.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAdultAerobicAffectAmyotrophic Lateral SclerosisAnesthesia proceduresAspiration PneumoniaBackBehaviorBehavioralBrainBrain StemBrain-Derived Neurotrophic FactorBreathingCholera ToxinClinicalDataDeglutitionDeglutition DisordersDependenceDevelopmentDisease ProgressionDisease modelElectrophysiology (science)Enteral FeedingExerciseFluoroscopyFunctional disorderFutureGoalsHistologicHypertrophyImmunohistochemistryImpairmentInjectionsKennedy SyndromeKnowledgeLifeLimb structureLungMagnetic Resonance ImagingModelingMolecularMotorMotor CortexMotor Neuron DiseaseMotor NeuronsMotor outputMovementMuscleNerveNeuronal PlasticityNeuronsPalliative CarePathologyPatientsPatternPhysical ExercisePilot ProjectsPlethysmographyPneumoniaPseudobulbar PalsyQuality of lifeRattusResistanceRespiratory FailureRoleStructureSynapsesTestingTherapeuticTongueTransmission Electron MicroscopyUp-RegulationVascular Endothelial Growth FactorsVentilatorWhole Body PlethysmographyWorkaspiratecell motilitydysphagia rehabilitationeffective therapyexercise trainingfunctional improvementfunctional outcomesgenioglossus muscleimprovedin vivointerdisciplinary approachmotor neuron degenerationneuroimagingneuron lossneurotrophic factornovelorofacialpharmacologicpreservationrepairedresistance exerciserespiratoryresponsetargeted treatmenttranslational studytreatment effectwhite matter
项目摘要
Motor neuron diseases (e.g., amyotrophic lateral sclerosis/ALS, pseudobulbar palsy, and Kennedy’s disease)
result in life-threatening alterations in upper airway function (i.e., swallowing and breathing) primarily due to
degeneration within the hypoglossal (XII) axis. This includes upper motor neurons (UMNs) in the orofacial region
of the primary motor cortex (MIo), lower motor neurons (LMNs) in the brainstem, and the tongue muscles.
Despite its critical importance, upper airway function has seldom been studied in motor neuron diseases; thus,
effective treatments remain to be discovered. The fundamental goals of this study are to understand how
XII axis degeneration impairs the function and coordination of swallowing and breathing, and to
determine if (and how) tongue exercise alters XII axis deficits in a novel model of XII motor neuron death.
This unique model is induced by intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) to
cause XII motor neuron death, decreased XII motor output, degenerative changes in the XII nerve and
genioglossus (muscle innervated by the XII nerve), and corresponding decreased tongue motility and swallowing
rate, thus mimicking aspects of dysphagia in motor neuron diseases. Further, we have exciting new pilot data
suggesting that tongue exercise in CTB-SAP treated rats remarkably preserves tongue strength and motility as
well as swallowing and breathing patterns/coordination similar to controls. Here we will test the central
hypothesis that upper airway function/coordination can be preserved in the face of XII motor neuron
degeneration by harnessing the therapeutic potential of tongue exercise to upregulate neuroplasticity
via neurotrophic factor expression in spared XII axis motor neurons. We will test this hypothesis in our
novel CTB-SAP rat model using a translational, non-invasive therapeutic strategy of resistance tongue exercise
training, and a multidisciplinary approach involving whole body plethysmography, videofluoroscopic swallow
studies, force lickometer testing, XII nerve and evoked swallowing electrophysiological recordings, in vivo
pharmacological manipulations, histological assessments (immunohistochemistry and transmission electron
microscopy), and neuroimaging (magnetic resonance imaging). Two specific aims are proposed after intralingual
CTB-SAP injections to determine: 1) how swallowing and breathing patterns/coordination are altered by XII axis
degeneration; and 2) the impact of tongue exercise on XII axis deficits and the role of neurotrophic factors. Since
most patients with motor neuron disease develop upper airway dysfunction leading to ventilator and/or feeding-
tube dependence, our long-range goal is to develop new strategies to enhance the functional capacity of spared
XII motor neurons to improve functional outcomes. If successful, this work will identify behavioral (tongue
exercise) and molecular (e.g., neurotrophic factor) strategies for future translational studies to preserve upper
airway function in patients with motor neuron diseases to significantly improve the quality and duration of life.
运动神经元疾病(例如,肌萎缩侧索硬化症/ALS、假性延髓麻痹和肯尼迪病)
导致危及生命的上呼吸道功能改变(即,呼吸和吞咽),主要是由于
舌下神经(XII)轴内的变性。这包括口面部区域的上运动神经元(UMN)
初级运动皮层(MIo),脑干中的下运动神经元(LMN)和舌肌。
尽管上呼吸道功能至关重要,但很少在运动神经元疾病中进行研究;因此,
有效的治疗方法仍有待发现。这项研究的基本目标是了解如何
XII轴变性损害吞咽和呼吸的功能和协调,
确定舌头运动是否(以及如何)改变XII运动神经元死亡的新模型中的XII轴缺陷。
这种独特的模型是通过舌内注射与皂草素缀合的霍乱毒素B(CTB-SAP)诱导的,
导致XII运动神经元死亡,XII运动输出减少,XII神经退行性变化,
颏舌肌(由XII神经支配的肌肉),以及相应的舌头运动和吞咽减少
速率,从而模仿运动神经元疾病中吞咽困难的方面。此外,我们有令人兴奋的新的试点数据,
提示CTB-SAP治疗的大鼠的舌运动显著地保持了舌的强度和运动性,
以及吞咽和呼吸模式/协调类似于对照。在这里,我们将测试中央
上呼吸道功能/协调可以在XII运动神经元面中保留假设
通过利用舌头运动的治疗潜力来上调神经可塑性,
通过神经营养因子在备用的XII轴运动神经元中的表达。我们将在我们的
使用阻力舌运动转化、非侵入性治疗策略的新型CTB-SAP大鼠模型
培训和多学科方法,包括全身体积描记术、视频荧光透视吞咽
研究,力舔测试,XII神经和诱发吞咽电生理记录,在体内
药理学操作,组织学评估(免疫组织化学和透射电子显微镜)
显微镜)和神经成像(磁共振成像)。两个具体的目标后,提出了语内
CTB-SAP注射以确定:1)吞咽和呼吸模式/协调如何被XII轴改变
2)舌运动对XII轴缺陷的影响和神经营养因子的作用。以来
大多数患有运动神经元疾病的患者发展上呼吸道功能障碍,导致呼吸机和/或进食,
管依赖,我们的长远目标是制定新的战略,以提高功能能力的备用
第十二运动神经元,以改善功能的结果。如果成功,这项工作将确定行为(舌头)
运动)和分子(例如,神经营养因子)的策略,为未来的翻译研究,以保持上层
气道功能明显改善运动神经元疾病患者的生活质量和生存时间。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tongue and hypoglossal morphology after intralingual cholera toxin B-saporin injection.
- DOI:10.1002/mus.27131
- 发表时间:2021-03
- 期刊:
- 影响因子:3.4
- 作者:Lind LA;Lever TE;Nichols NL
- 通讯作者:Nichols NL
Minimally Invasive Murine Laryngoscopy for Close-Up Imaging of Laryngeal Motion during Breathing and Swallowing.
微创小鼠喉镜用于呼吸和吞咽过程中喉部运动的特写成像。
- DOI:10.3791/66089
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Lever,TeresaE;Kloepper,Ashley;Welby,Lauren;Haney,Megan;Fudge,Shakera;Seiller,Chase;Kington,Sophia;Ballenger,Brayton;Nichols,NicoleL
- 通讯作者:Nichols,NicoleL
Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS.
- DOI:10.1007/s00455-022-10442-4
- 发表时间:2022-12
- 期刊:
- 影响因子:2.6
- 作者:
- 通讯作者:
A Strength Endurance Exercise Paradigm Mitigates Deficits in Hypoglossal-Tongue Axis Function, Strength, and Structure in a Rodent Model of Hypoglossal Motor Neuron Degeneration.
- DOI:10.3389/fnins.2022.869592
- 发表时间:2022
- 期刊:
- 影响因子:4.3
- 作者:Murphy, Erika R.;Thompson, Rebecca;Osman, Kate L.;Haxton, Chandler;Brothers, Margaret;Lee, Li;Warncke, Kristen;Smith, Catherine L.;Keilholz, Amy N.;Hamad, Ali;Golzy, Mojgan;Bunyak, Filiz;Ma, Lixin;Nichols, Nicole L.;Lever, Teresa E.
- 通讯作者:Lever, Teresa E.
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TERESA E LEVER其他文献
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{{ truncateString('TERESA E LEVER', 18)}}的其他基金
Targeted neuromodulation strategies to delay hypoglossal motoneuron death and preserve tongue strength, function, and structure in a mouse model of ALS
延缓 ALS 小鼠模型舌下运动神经元死亡并保持舌头力量、功能和结构的靶向神经调节策略
- 批准号:
10527999 - 财政年份:2022
- 资助金额:
$ 50.02万 - 项目类别:
Harnessing tongue exercise to enhance neuroplasticity and preserve upper airway function in a novel model of hypoglossal motor neuron degeneration
在舌下运动神经元变性的新型模型中利用舌头运动增强神经可塑性并保留上呼吸道功能
- 批准号:
10433920 - 财政年份:2020
- 资助金额:
$ 50.02万 - 项目类别:
Harnessing tongue exercise to enhance neuroplasticity and preserve upper airway function in a novel model of hypoglossal motor neuron degeneration
在舌下运动神经元变性的新型模型中利用舌头运动增强神经可塑性并保留上呼吸道功能
- 批准号:
10033555 - 财政年份:2020
- 资助金额:
$ 50.02万 - 项目类别:
Harnessing tongue exercise to enhance neuroplasticity and preserve upper airway function in a novel model of hypoglossal motor neuron degeneration
在舌下运动神经元变性的新型模型中利用舌头运动增强神经可塑性并保留上呼吸道功能
- 批准号:
10380956 - 财政年份:2020
- 资助金额:
$ 50.02万 - 项目类别:
Development of swallow evoked potentials as a novel tool to investigate swallowin
吞咽诱发电位的开发作为研究吞咽的新工具
- 批准号:
7883020 - 财政年份:2010
- 资助金额:
$ 50.02万 - 项目类别:
Development of swallow evoked potentials as a novel tool to investigate swallowin
吞咽诱发电位的开发作为研究吞咽的新工具
- 批准号:
8063194 - 财政年份:2010
- 资助金额:
$ 50.02万 - 项目类别:
Development of swallow evoked potentials as a novel tool to investigate swallowin
吞咽诱发电位的开发作为研究吞咽的新工具
- 批准号:
8286820 - 财政年份:2010
- 资助金额:
$ 50.02万 - 项目类别:
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