Neural mechanisms of age-related weakness
年龄相关性无力的神经机制
基本信息
- 批准号:10733022
- 负责人:
- 金额:$ 65.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcuteAgingAgonistAnimalsChronicClinicalClinical ResearchCre lox recombination systemDataDoseElderlyExhibitsExtensorFutureGenerationsGeneticHand StrengthHealthHumanImpairmentInjuryInterventionIsotonic ExerciseLegLevel of EvidenceLinkLongevityLongitudinal StudiesMissionModelingMotorMotor NeuronsMusMusclePhenotypePublic HealthRattusReportingResearchRodentRoleSepsisSerotoninSerotonin Receptor 5-HT2CShapesTamoxifenTestingThigh structureThinnessTranslatingUnited States National Institutes of HealthWorkage relatedage-related muscle lossageddesignexperimental studyhuman datahuman old age (65+)indexinginsightlongitudinal designmotor disordermuscle formmuscle strengthneuralneuromechanismneuronal excitabilitypharmacologicphysically handicappedpre-clinicalresponseseptictreatment strategy
项目摘要
ABSTRACT
More than 40% of older adults (OAs) report limitations to performing tasks that are essential to maintain
independence. Weakness is an important contributor to physical impairments; indeed, weakness predisposes
OAs to a four-fold increase in physical limitations. Because strength is a vital factor for health and longevity,
more comprehensive understanding of the causes of weakness is needed to develop targeted interventions to
enhance strength and function in OAs. While age-related loss of muscle mass and quality are partly responsible
for weakness, there is increasing evidence that deficits in neural activation are critically linked to age-related
weakness. In particular, we and others have demonstrated that weakness associated with aging and other
conditions (e.g., disuse, injury, sepsis) is due, in part, to neural hypoexcitability. In this application, we seek to
fundamentally advance our understanding of the mechanisms of and treatment strategies for age-related
weakness and mobility limitations through translational human (Aim 1) and pre-clinical rodent (Aim 2)
experiments that, collectively, will provide strong data indicating a causal association between neural
hypoexcitability and age-related weakness. The first aim will test the hypothesis that indices of neural
hypoexcitability are associated with greater future (longitudinal) losses of strength in OAs. Here, we will leverage
data from a prior R01 to conduct a longitudinal study in humans where we quantify indices of neural excitability,
lean mass, strength, and mobility after ~ 8-years in older adults. These data will be used to determine the relative
contribution of indices of neural excitability and thigh lean mass on future decline in muscle strength in older
adults, with a robust design accounting for alternative mechanisms. By using a longitudinal design in humans,
this aim will provide the strongest level of evidence for neural excitability being a key predictor of age-related
strength loss, which is a paradigm shift away from the current consideration of primarily muscular factors (e.g.,
muscle mass). The second aim will consist of four experiments. Experiments 1-3 will use a 5-HT2c agonist
(lorcaserin) with a well-known mechanism of action that increases persistent inward currents and motoneuron
excitability. SA2.1 will test the hypothesis that there is an inverted U-shape relationship between 5-HT2c agonist
dose and motor function response in old mice. SA2.2 will test the hypothesis that a 5-HT2c agonist will enhance
motor function in aged mice by increasing neural excitation to demonstrate that the reduction in MN excitability
is a significant contributor to motor dysfunction in old mice. SA2.3 will test chronic effects of lorcaserin treatment
on motor unit number and function in aged mice. SA2.4 will test the impact of tamoxifen-inducible genetic deletion
of 5-HT2c receptors in MNs using Cre-Lox system. In the long-term, this proof-of-concept, proof-of-mechanism
work could serve as evidence for a neurotherapeutic agent to enhance motor function in older adults.
摘要
超过40%的老年人(OA)报告在执行对维护至关重要的任务时受到限制
独立。虚弱是身体损伤的一个重要因素;事实上,虚弱是
OAS的物理限制增加了四倍。因为力量是健康和长寿的重要因素,
需要更全面地了解虚弱的原因,以制定有针对性的干预措施
增强OAS的实力和功能。而与年龄相关的肌肉质量和质量的丧失是部分原因
对于虚弱,越来越多的证据表明,神经激活缺陷与年龄相关
软弱。特别是,我们和其他人已经证明了与衰老和其他
情况(例如,停用、损伤、败血症)部分是由于神经兴奋性低下。在此应用程序中,我们寻求
从根本上促进我们对年龄相关性疾病的发病机制和治疗策略的理解
转化人(目标1)和临床前啮齿动物(目标2)的虚弱和活动受限
这些实验将共同提供强有力的数据,表明神经之间的因果联系
兴奋性不足和年龄相关的虚弱。第一个目标将检验这样一个假设,即神经指数
低兴奋性与OAS中更大的未来(纵向)力量损失有关。在这里,我们将利用
来自之前的R01的数据,在人类中进行一项纵向研究,其中我们量化神经兴奋性的指数,
老年人在8年后体重、力量和活动能力都会变瘦。这些数据将被用来确定
神经兴奋性和大腿瘦体重指数对老年人未来肌力下降的贡献
成年人,具有考虑到替代机制的健壮设计。通过在人体上使用纵向设计,
这一目标将为神经兴奋性是年龄相关的关键预测因子提供最有力的证据
力量丧失,这是对当前主要考虑肌肉因素的范式的转变(例如,
肌肉质量)。第二个目标将由四个实验组成。实验1-3将使用5-HT2C激动剂
(氯酪蛋白)具有众所周知的作用机制,可增加持续的内向电流和运动神经元
兴奋性。SA2.1将检验5-HT2C激动剂之间存在倒U型关系的假设
老年小鼠的剂量和运动功能反应。SA2.2将测试5-HT2C激动剂将增强
老年小鼠运动功能通过增加神经兴奋性来证明MN兴奋性的降低
是导致老年小鼠运动功能障碍的重要因素。SA2.3将测试氯卡韦林治疗的慢性影响
老年小鼠运动单位数目和功能的研究。SA2.4将测试他莫昔芬诱导的基因缺失的影响
用Cre-Lox系统检测MNS中5-HT2C受体的表达。从长远来看,这种概念证明、机制证明
这项研究可以作为神经治疗剂增强老年人运动功能的证据。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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William David Arnold其他文献
William David Arnold的其他文献
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{{ truncateString('William David Arnold', 18)}}的其他基金
Accurate and rapid assessment of sarcopenia in older adults through electrical impedance myography
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- 批准号:
10484558 - 财政年份:2022
- 资助金额:
$ 65.05万 - 项目类别:
Accurate and rapid assessment of sarcopenia in older adults through electrical impedance myography
通过电阻抗肌电图准确快速评估老年人肌少症
- 批准号:
10668482 - 财政年份:2022
- 资助金额:
$ 65.05万 - 项目类别:
Accurate and rapid assessment of sarcopenia in older adults through electrical impedance myography - Development of Regulatory Plans Supplement
通过电阻抗肌动描记法准确、快速地评估老年人的肌少症 - 制定监管计划补充材料
- 批准号:
10700526 - 财政年份:2022
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$ 65.05万 - 项目类别:
Motoneuronal mechanisms underlying age-related muscle weakness
年龄相关性肌肉无力的运动神经机制
- 批准号:
10810941 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Motoneuronal mechanisms underlying age-related muscle weakness
年龄相关性肌肉无力的运动神经机制
- 批准号:
10407020 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Motoneuronal mechanisms underlying age-related muscle weakness
年龄相关性肌肉无力的运动神经机制
- 批准号:
10612078 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Motoneuronal mechanisms underlying age-related muscle weakness
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10618019 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Motoneuronal mechanisms underlying age-related muscle weakness
年龄相关性肌肉无力的运动神经机制
- 批准号:
10543345 - 财政年份:2021
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$ 65.05万 - 项目类别:
Motoneuronal mechanisms underlying age-related muscle weakness
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10057744 - 财政年份:2020
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