Role of Central Autonomic Relays in Aging Sarcopenia
中枢自主神经继电器在老年性肌肉减少症中的作用
基本信息
- 批准号:10363160
- 负责人:
- 金额:$ 59.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-15 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:4-ethoxymethylene-2-phenyl-2-oxazoline-5-oneAdrenergic ReceptorAffectAgeAgingAttenuatedAxonCell NucleusChronicCollectionDataDenervationDevelopmentDiseaseElderlyFailureG-Protein-Coupled ReceptorsGene ExpressionGene Expression ProfilingGene SilencingGenesHalorhodopsinsHealthHindlimbHomeoboxImaging TechniquesImpairmentInterventionLabelMeasuresMediatingMethylationMolecularMolecular TargetMonitorMotorMotor NeuronsMusMuscleMuscle FibersMuscle functionMuscular AtrophyNeurodegenerative DisordersNeuromuscular JunctionNeuronsNeurotransmittersNorepinephrinePatch-Clamp TechniquesPeripheralPhysiologicalPontine structureProteinsPublishingQuality of lifeReactionRegulationRoleSignal TransductionSkeletal MuscleSpinal CordSympathetic Nervous SystemSympathomimeticsSynaptic VesiclesTRPV1 geneTestingTimeTissuesTranscriptWasting Syndromeage relatedbasedelivery vehicledemethylationdesigndisabilityextracellularhuman old age (65+)improvedinnovationlight gatedmotor controlmuscle formmuscular structurenerve supplynovel strategiesoptogeneticsphysiologic stressorpostsynapticpresynapticprotein expressionretrograde transportsarcopeniaside effecttooltranscription factortranscriptome sequencingtransmission processvectorvesicular releasevoltage
项目摘要
Summary:
SNS failure is common in old age and neurodegenerative diseases that impair adaptation to common
physiological stressors. We and others found that sympathetic axons innervate skeletal muscle fibers and
maintain the integrity of skeletal muscle composition and function at the presynaptic and postsynaptic
neuromuscular junction (NMJ) in health and disease. We also demonstrated that (a) SNS impairment leads to
skeletal muscle motor denervation; (b) both the SNS and sympathomimetics regulate motoneuron synaptic
vesicle release and postsynaptic molecular composition; and (c) aging blunts the influence of the SNS on NMJ
transmission. These data support the strong influence of the SNS on motoneuron and myofiber molecular
composition and function.
Probing deeper, we found that the SNS and sympathomimetics regulate motoneuron synaptic vesicle release
via extracellular Ca2+ and such molecular targets, as TRPV1 and P/Q- and N-type voltage-activated Ca2+
channels. Recently, we demonstrated that ?1-adrenoceptor is expressed in motoneurons and declines
significantly with aging. These studies unveil the molecular substrate that accounts for the influence of
peripheral sympathetic neurons on NMJ transmission in young mice and its decline with aging. However, we
do not know whether and how the central autonomic relays (CARs)—particularly the pontine A5 nucleus, which
projects to the spinal cord intermediolateral (IML) column—regulate skeletal muscle mass, strength,
innervation, and NMJ transmission and whether this influence declines over time. Optogenetics combined with
neuron retrograde labeling provides a unique opportunity to determine the precise role of A5 nucleus in living
mice.
Based on our published and preliminary data, we propose that aging impairs A5 nucleus regulation of
the peripheral SNS, increasing skeletal muscle sympathetic and motor denervation and loss of mass
and strength.
The following specific aims are designed to test this hypothesis: Aim 1 define the role of A5 sympathetic
neurons projecting to hindlimb muscles (SNPHLM) in muscle motoneuron denervation, impaired NMJ
transmission, and sarcopenia with aging, and Aim 2 will determine whether sustained expression of the master
sympathetic transcription factor Phox-2b in A5 SNPHLM attenuates skeletal muscle sympathetic and motor
denervation with aging.
This project will be the first to define CARs’ role in NMJ transmission and muscle sympathetic and motor
innervation. It will elucidate upper level control of the motor unit to achieve an integrated, comprehensive
understanding of aging sarcopenia. Successful results will shift the treatment target for sarcopenia from the
skeletal muscle to the central sympathetic neuron.
摘要:
SNS失败在老年和神经退行性疾病中很常见,这些疾病损害了对共同
生理压力源。我们和其他人发现交感神经轴突支配骨骼肌纤维和
在突触前和突触后维持骨骼肌组成和功能的完整性
神经肌肉接头(NMJ)与健康和疾病我们还证明:(A)SNS功能受损会导致
骨骼肌运动失神经;(B)三叉神经节和拟交感神经对运动神经元突触的调节
囊泡释放和突触后分子组成;以及(C)衰老减弱了SNS对NMJ的影响
变速箱。这些数据支持了SNS对运动神经元和肌纤维分子的强烈影响
组成和功能。
进一步研究,我们发现SNS和拟交感神经调节运动神经元突触小泡的释放
通过细胞外钙离子和TRPV1、P/Q和N型电压激活的钙离子等分子靶点
频道。最近,我们发现?1-肾上腺素能受体在运动神经元中表达,并呈递减趋势。
随着年龄的增长显著增加。这些研究揭示了分子底物,它解释了
幼年小鼠外周交感神经元对NMJ传递的影响及其随年龄的下降。然而,我们
不知道中枢自主神经是否和如何传递(CARS)--特别是桥脑A5核,它
投射到脊髓中间外侧(IML)柱-调节骨骼肌质量,力量,
神经支配和NMJ传递,以及这种影响是否会随着时间的推移而减弱。光遗传学与
神经元逆行标记为确定A5核在生活中的确切作用提供了一个独特的机会
老鼠。
根据我们已发表的和初步的数据,我们认为衰老损害了A5核对
外周SNS,增加骨骼肌交感神经和运动神经的失神经和质量损失
和力量。
以下具体目标旨在检验这一假设:目标1定义A5交感神经的作用
NMJ受损肌肉运动神经元失神经投射到后肢肌肉的神经元(SNPHLM)
随着年龄的增长,骨质疏松症的持续表达和目标2将决定是否持续表达的主人
A5SNPHLM中交感转录因子Phox-2b减弱骨骼肌交感神经和运动
随着年龄的增长而丧失神经。
这个项目将第一次定义汽车在NMJ传递以及肌肉交感和运动中的作用
神经支配。它将阐述对电机单元的上层控制,实现一体化、全面化
对老年性石棺减少症的认识。成功的结果将使石棺减少症的治疗目标从
从骨骼肌到中枢交感神经元。
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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Osvaldo Delbono其他文献
Osvaldo Delbono的其他文献
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{{ truncateString('Osvaldo Delbono', 18)}}的其他基金
Accelerated Sarcopenia in Early Alzheimer's Disease
早期阿尔茨海默病加速肌肉减少症
- 批准号:
10589353 - 财政年份:2022
- 资助金额:
$ 59.41万 - 项目类别:
Role of Central Autonomic Relays in Aging Sarcopenia
中枢自主神经继电器在老年性肌肉减少症中的作用
- 批准号:
10569556 - 财政年份:2022
- 资助金额:
$ 59.41万 - 项目类别:
The Role of the Sympathetic Nervous System in the Onset and Development of Sarcopenia
交感神经系统在肌少症发生和发展中的作用
- 批准号:
9921285 - 财政年份:2017
- 资助金额:
$ 59.41万 - 项目类别:
The Role of the Sympathetic Nervous System in the Onset and Development of Sarcopenia
交感神经系统在肌少症发生和发展中的作用
- 批准号:
9386285 - 财政年份:2017
- 资助金额:
$ 59.41万 - 项目类别:
The Role of the Sympathetic Nervous System in the Onset and Development of Sarcopenia
交感神经系统在肌少症发生和发展中的作用
- 批准号:
10180828 - 财政年份:2017
- 资助金额:
$ 59.41万 - 项目类别:
Administrative Research Supplement to Promote Diversity in Health-Related Research
促进健康相关研究多样性的行政研究补充
- 批准号:
10227360 - 财政年份:2017
- 资助金额:
$ 59.41万 - 项目类别:
Role of Calcium Channels in Aging Skeletal Muscle
钙通道在骨骼肌衰老中的作用
- 批准号:
8207958 - 财政年份:2009
- 资助金额:
$ 59.41万 - 项目类别:
Role of Calcium Channels in Aging Skeletal Muscle
钙通道在骨骼肌衰老中的作用
- 批准号:
8010208 - 财政年份:2009
- 资助金额:
$ 59.41万 - 项目类别:
Role of Calcium Channels in Aging Skeletal Muscle
钙通道在骨骼肌衰老中的作用
- 批准号:
7764524 - 财政年份:2009
- 资助金额:
$ 59.41万 - 项目类别:
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