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
• 负责人: Osvaldo Delbono
• 金额: $ 4.37万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227360
• 关键词: Age; Aging; Autophagocytosis; Axon; Basic Science; Cholinergic Receptors; Chronic; Data; Denervation; Development; Elderly; Elements; Failure; Fiber; Funding; Health; Human; Impairment; Intervention; Link; Maintenance; Modeling; Motor; Motor Neurons; Mus; Muscle; Muscle denervation procedure; Muscle function; Nervous system structure; Neuromuscular Junction; Neurons; Peripheral Nervous System; Play; Process; Quality of life; Regulation; Research; Rodent; Role; Schwann Cells; Secondary to; Skeletal Muscle; Sympathectomy; Sympathetic Nervous System; Synapses; System; Testing; Time; Training; Translational Research; Ubiquitin; Viral; age related; base; design; multicatalytic endopeptidase complex; muscle form; muscular structure; nerve supply; neuron development; novel; parent grant; parent project; postsynaptic; preservation; presynaptic; prevent; reduced muscle mass; reinnervation; relating to nervous system; sarcopenia; skeletal preservation; transcription factor; transmission process

PROJECT SUMMARY: Over time, declining muscle force and power impair mobility and quality of life. In aging rodents and humans, skeletal muscle undergoes a process of denervation and reinnervation; denervation is strongly implicated in the onset and progressive decline of skeletal muscle mass, composition, and function, termed sarcopenia. Whether muscle denervation starts at the myofiber or the central or peripheral nervous system is controversial. Answering this question is crucial for developing targeted interventions to prevent or reverse age-related decline in skeletal muscle innervation and consequent loss of mass and force. Increasing evidence supports a decline in neural influence on skeletal muscle at older ages. The neuromuscular junction (NMJ) is a tripartite synapse composed of the presynaptic motor neuron axon, postsynaptic myofiber specialization, and nonmyelinating perisynaptic or terminal Schwann cells (tSCs). With age, the NMJ becomes unstable in a process characterized by fragmentation, shrinkage, and simplification of the postterminal. Detailed studies indicate that the tripartite model includes elements that are crucial for normal skeletal muscle structure and function, so why, does the normally stable NMJ eventually destabilize? In humans, autonomic innervation and function become impaired with age. Our preliminary data support direct sympathetic innervation of the myofiber at the NMJ, sympathetic regulation of motor/somatic fiber innervation, and regulation of muscle autophagy with aging. Based on our novel preliminary data, we hypothesize that: (1) Hand2, a key transcription factor for sympathetic neuron development and maintenance, steeply declines with aging, inducing motor pre- and postsynaptic NMJ instability and disorganization, muscle denervation, and sarcopenia; and (2) Expressing Hand2 exclusively in sympathetic neurons will significantly prevent: (a) motor denervation, (b) increased ubiquitin-proteasome system (UPS) activity, (c) impaired autophagy and NMJ transmission, and (d) sarcopenia, in old (22-month) and geriatric (28-month) mice. The following specific aims are designed to test these hypotheses: Aim 1. To determine whether age-dependent sympathetic denervation causes motor denervation, NMJ disorganization and transmission failure, and sarcopenia. Aim 2. To establish whether preserving muscle sympathetic innervation prevents increased UPS, decreased autophagy flux, decreased acetylcholine receptor (AChR), and muscle motor denervation with aging. This project will be the first to define the link between two hallmarks of aging skeletal muscle—denervation and sarcopenia—and the cross-talk between the sympathetic and motor nervous systems at the skeletal muscle with aging.

项目摘要： 随着时间的流逝，肌肉力量和力量下降会损害流动性和生活质量。在老化的啮齿动物和人类中， 骨骼肌经历了神经支配和加重过程。改造的强烈牵涉 骨骼肌质量，组成和功能的发作和逐渐下降称为肌肉减少症。 肌肉神经支配是从肌纤维还是中央神经系统或周围神经系统开始的。 回答这个问题对于制定有针对性的干预措施以防止或逆转年龄有关 骨骼肌神经支配的下降以及随之而来的质量和力损失。 越来越多的证据支持神经对老年骨骼肌的影响下降。这 神经肌肉连接（NMJ）是由突触前运动神经元轴突组成的三方突触 突触后肌纤维的专业化以及非催化性直发或末端Schwann细胞（TSC）。和 年龄，NMJ在以分裂，收缩和简化为特征的过程中变得不稳定 后末期。详细的研究表明，三岩模型包括对正常至关重要的元素 骨骼肌结构和功能，为什么通常稳定的NMJ最终会破坏稳定？在 人类，自主神经支配和功能会随着年龄的增长而受到损害。我们的初步数据支持直接 NMJ在NMJ上的同情神经，运动/体细胞神经支配的同情调节， 和肌肉自噬随老化的调节。根据我们新颖的初步数据，我们假设： （1）Hand2，是交感神经元发展和维护的关键转录因子，钢铁 随着衰老而下降，诱导运动前和突触后NMJ的不稳定性和混乱， 肌肉改造和肌肉减少症；和 （2）独家在交感神经元中表达手2将大大预防：（a）电动机 改造，（b）增加泛素 - 蛋白酶体系统（UPS）活动，（c）自噬和 NMJ传播和（D）肌肉减少症，旧（22个月）和老年（28个月）小鼠。 以下特定目标旨在检验这些假设： 目的1。确定年龄依赖性的交感神经是否引起运动神经支配，NMJ 混乱和传播故障以及肌肉减少症。 目标2。确定保存肌肉交感神经是否可以阻止增加的情况， 自噬通量减少，乙酰胆碱受体（ACHR）和肌肉运动神经神经支配减少 随着衰老。 该项目将是第一个定义衰老骨骼肌肉两个标志的连接的项目： 肌肉减少症 - 骨骼肌的交感神经和运动神经系统之间的串扰 随着衰老。