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
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
通过电阻抗肌电图准确快速评估老年人肌少症
- 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
- 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:
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:
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:
10612078 - 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
- 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:
10641197 - 财政年份:2021
- 资助金额:
$ 65.05万 - 项目类别:
Social Isolation and Loss of Physical Function: Defining a Novel Neuromuscular Phenotype
社会孤立和身体功能丧失:定义一种新的神经肌肉表型
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10057744 - 财政年份:2020
- 资助金额:
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