FBT-PET Study of Aging Skeletal Muscle

衰老骨骼肌的 FBT-PET 研究

• 批准号: 7758242
• 负责人: Osvaldo Delbono
• 金额: $ 18.03万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758242
• 关键词: 3-Dimensional; Age; Age-Months; Aging; Aging-Related Process; Animals; Area; Atrophic; Autoradiography; Binding; Blood Vessels; Brain; Bungarotoxins; Caloric Restriction; Chronic; Data; Denervation; Elderly; Evaluation; Excision; Fiber; Hindlimb; Human; Imaging Techniques; Immunohistochemistry; In Vitro; Institution; Intervention; Label; Magnetic Resonance Imaging; Measurement; Measures; Motor; Motor Neurons; Mus; Muscle; Muscle denervation procedure; Muscle function; Natural History; Needle biopsy procedure; Nerve; Nerve Degeneration; Neuromuscular Junction; Organ; Outcome Study; Phase; Positron-Emission Tomography; Preparation; Research; Rodent; Role; Signal Transduction; Skeletal Muscle; Specificity; Spinal Cord; Staining method; Stains; Techniques; Testing; Time; Tissues; Translating; Validation; acetylcholine transporter; age related; density; disability; feeding; follow-up; functional decline; in vivo; intervention effect; knock-down; molecular imaging; nerve supply; neuron loss; novel; prevent; public health relevance; radioligand; radiotracer; sarcopenia; tool; uptake; vesamicol; young adult

DESCRIPTION (provided by applicant): This project responds to RFA-DA-001. Its objective is to extend the utility of positron emission tomography (PET) flurobenzyltrozamicol (FBT) radioligand in the study of brain to the study of aging skeletal muscle. Growing evidence supports a role for neural degeneration in the chronic, age-related structural and functional decline of skeletal muscle. It will test the hypothesis that the noninvasive imaging procedure FBT-PET can be used to assess skeletal muscle innervation throughout the aging process in rodents. Results will inform an analysis of its role in human sarcopenia. The following specific aims will be analyzed in young adult (7-month) and aged (24-month) mice fed ad libitum and calorie-restricted, a maneuver known to retard motor neuron loss with aging. Specific Aim 1. To quantify hindlimb muscle innervation using FBT-PET. Time/activity curves in lower hindlimb muscles and differences in FBT uptake between three experimental groups will be measured. Loss of muscle volume with aging will be analyzed by MRI. FBT-PET and MRI signals will be co-registered. Signal specificity will be analyzed by measuring: (a) FBT vascular clearance, (b) [3H]FBT binding, (c) [3H]FBTautoradiography, (d) blocking of 18F-FBT uptake with cold FBT/vesamicol, and (e) FBT uptake by VAChT knock-down mice. Specific Aim 2. To examine the relationship between FBT-PET and mouse skeletal muscle function in vivo and in vitro using a well-characterized functional assessment battery and single muscle force measurement, respectively. These studies will determine a relationship between age-related decrease in muscle function and the magnitude and extension of muscle denervation. Specific Aim 3. To quantify mouse muscle VAChT density using in vitro determinations and to establish a relationship with FBT-PET. Immunohistochemistry (IH) for VAChT will allow us to measure the transporter's density in multiple sections of longitudinal muscle. IH signal specificity will be determined by double staining with labeled a-bungarotoxin, which stains the post-terminal AChR. PUBLIC HEALTH RELEVANCE: The contribution of muscle denervation to sarcopenia remains elusive, particularly in humans. Validation of FBT (flurobenzyltrozamicol)-Positron Emission Tomography (PET) as a novel, accurate, noninvasive measure of skeletal muscle innervation in rodents will provide valuable data that can be rapidly translated into an effective research tool in animals and humans. Clinically, it can be used to evaluate interventions aimed at preventing and/or ameliorating the contribution of muscle denervation to sarcopenia and subsequent physical disability in the elderly. Results of this project are intended to inform the preparation and submission of applications necessary to gain regulatory approval to examine skeletal muscle denervation and its influence on sarcopenia in humans. In a second phase, distribution of the radiotracer FBT to other institutions will allow a multi-center evaluation of its utility in quantifying muscle denervation associated with human sarcopenia.

描述（由申请人提供）：该项目响应 RFA-DA-001。其目的是将正电子发射断层扫描 (PET) 氟苄基三唑胺 (FBT) 放射性配体在大脑研究中的用途扩展到衰老骨骼肌的研究。越来越多的证据支持神经退行性变在骨骼肌慢性、与年龄相关的结构和功能衰退中的作用。它将检验以下假设：无创成像程序 FBT-PET 可用于评估啮齿类动物整个衰老过程中的骨骼肌神经支配。结果将有助于分析其在人类肌肉减少症中的作用。 以下具体目标将在年轻成年（7 个月）和老年（24 个月）小鼠中进行分析，这些小鼠随意喂养并限制热量，这种策略已知可以延缓衰老过程中运动神经元的损失。 具体目标 1. 使用 FBT-PET 量化后肢肌肉神经支配。将测量下后肢肌肉的时间/活动曲线以及三个实验组之间 FBT 摄取的差异。将通过 MRI 分析随年龄增长而出现的肌肉体积损失。 FBT-PET 和 MRI 信号将被共同注册。将通过以下测量来分析信号特异性：(a)FBT血管清除率，(b)[3H]FBT结合，(c)[3H]FBT放射自显影，(d)用冷FBT/维沙考阻断18F-FBT摄取，和(e)VAChT敲低小鼠的FBT摄取。 具体目标 2. 分别使用充分表征的功能评估电池和单次肌肉力测量来检查体内和体外 FBT-PET 与小鼠骨骼肌功能之间的关系。这些研究将确定与年龄相关的肌肉功能下降与肌肉去神经支配的程度和范围之间的关系。 具体目标 3. 使用体外测定量化小鼠肌肉 VAChT 密度并建立与 FBT-PET 的关系。 VAChT 的免疫组织化学 (IH) 将使我们能够测量纵向肌肉多个部分中转运蛋白的密度。 IH 信号特异性将通过标记的α-金环蛇毒素双重染色来确定，该毒素对末端 AChR 进行染色。 公共卫生相关性：肌肉去神经支配对肌肉减少症的影响仍然难以捉摸，特别是在人类中。 FBT（氟苄基三唑胺）-正电子发射断层扫描 (PET) 作为一种新颖、准确、无创的啮齿动物骨骼肌神经支配测量方法的验证将提供有价值的数据，这些数据可以快速转化为动物和人类的有效研究工具。在临床上，它可用于评估旨在预防和/或改善肌肉去神经支配对老年人肌肉减少症和随后的身体残疾的影响的干预措施。该项目的结果旨在为获得监管部门批准检查骨骼肌去神经及其对人类肌肉减少症的影响所需的申请的准备和提交提供信息。在第二阶段，将放射性示踪剂 FBT 分发给其他机构将允许对其在量化与人类肌肉减少症相关的肌肉去神经支配方面的效用进行多中心评估。