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活动能力和生活质量。在老化的啮齿动物和人类中， 骨骼肌经历去神经支配和再神经支配的过程;去神经支配强烈地牵涉到 骨骼肌质量、组成和功能的发生和进行性衰退，称为肌肉减少症。 肌肉去神经是从肌纤维还是从中枢神经系统还是从外周神经系统开始存在争议。 解决这个问题对于制定有针对性的干预措施以预防或扭转与年龄有关的疾病至关重要。 骨骼肌神经支配的下降以及随之而来的质量和力量的损失。 越来越多的证据支持神经对骨骼肌的影响在老年时下降。的 神经肌肉接头（NMJ）是由突触前运动神经元轴突组成的三部分突触， 突触后肌纤维特化和非髓鞘化的突触周或末端施旺细胞（tSC）。与 随着年龄的增长，NMJ在一个以碎片化、收缩和简化为特征的过程中变得不稳定。 邮政终端。详细的研究表明，三方模式包括对正常生产至关重要的因素， 骨骼肌结构和功能，那么为什么，正常稳定的NMJ最终会不稳定？在 在人类中，自主神经支配和功能随着年龄的增长而受损。我们的初步数据直接支持 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神经调节， 以及肌肉自噬随衰老的调节。根据我们新的初步数据，我们假设： (1)Hand 2是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，诱导运动突触前和突触后NMJ不稳定和紊乱， 肌肉去神经支配和肌肉减少症;以及 (2)仅在交感神经元中表达Hand 2将显着阻止：（a）运动 去神经支配，（B）增加的泛素-蛋白酶体系统（UPS）活性，（c）受损的自噬和 NMJ传输，和（d）肌肉减少症，在老年（22个月）和老年（28个月）小鼠。 以下具体目标旨在检验这些假设： 目标1.为了确定年龄依赖性交感神经去神经是否会导致运动神经去神经，NMJ 组织混乱和传输失败以及肌肉减少症。 目标2.为了确定保留肌肉交感神经支配是否可以防止UPS增加， 减少自噬通量，减少乙酰胆碱受体（AChR），和肌肉运动去神经支配 随着年龄的增长。 这个项目将是第一个定义衰老骨骼肌的两个标志之间的联系-去神经支配和 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相互作用 随着年龄的增长。