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.

项目概要： 随着时间的推移，肌肉力量和力量的下降会损害老年啮齿动物和人类的活动能力和生活质量。 骨骼肌经历去神经支配和神经再支配的过程； 骨骼肌质量、成分和功能的发生和进行性下降，称为肌少症。 肌肉去神经支配是从肌纤维开始还是从中枢或周围神经系统开始尚存在争议。 回答这个问题对于制定有针对性的干预措施来预防或逆转与年龄有关的疾病至关重要 骨骼肌神经支配下降以及随之而来的质量和力量损失。 越来越多的证据支持老年人神经对骨骼肌的影响会下降。 神经肌肉接头（NMJ）是由突触前运动神经元轴突组成的三联突触， 突触后肌纤维特化和非髓鞘突触周围或终末雪旺细胞 (tSC)。 随着年龄的增长，NMJ 在一个以碎片、收缩和简化为特征的过程中变得不稳定。 详细的研究表明，三方模型包括对正常情况至关重要的要素。 骨骼肌的结构和功能，那么为什么通常稳定的NMJ最终会不稳定呢？ 人类的自主神经支配和功能会随着年龄的增长而受损。我们的初步数据直接支持这一点。 NMJ 处肌纤维的交感神经支配，运动/躯体纤维神经支配的交感调节， 根据我们新的初步数据，我们认为： (1) Hand2，交感神经元发育和维持的关键转录因子， 随着年龄的增长而下降，导致运动神经突触前和突触后 NMJ 不稳定和紊乱， 肌肉去神经支配和肌肉减少症； (2) 仅在交感神经元中表达 Hand2 将显着预防： 去神经支配，(b) 泛素蛋白酶体系统 (UPS) 活性增加，(c) 自噬受损和 在老年（22 个月）和老年（28 个月）小鼠中，NMJ 传播和 (d) 肌肉减少症。 以下具体目标旨在检验这些假设： 目标 1. 确定年龄依赖性交感神经去神经支配是否导致运动去神经支配，NMJ 紊乱和传输障碍，以及肌肉减少症。 目标 2. 确定交感肌神经支配是否会阻止 UPS 增加， 自噬通量减少、乙酰胆碱受体 (AChR) 减少和肌肉运动去神经支配 随着衰老。 该项目将首次定义骨骼肌衰老的两个特征——去神经支配和衰老之间的联系。 肌肉减少症——以及骨骼肌交感神经系统和运动神经系统之间的串扰 随着衰老。