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）：本项目响应RFA-DA-001。其目的是将正电子发射断层扫描（PET）氟苄基曲唑霉素（FBT）放射性配体在脑研究中的应用扩展到骨骼肌老化的研究。越来越多的证据支持神经退行性变在骨骼肌慢性、年龄相关的结构和功能衰退中的作用。它将测试的假设，即非侵入性成像程序FBT-PET可用于评估骨骼肌神经支配在整个老化过程中的啮齿动物。结果将告知其在人类肌肉减少症中的作用的分析。 将在年轻成年（7个月）和老年（24个月）小鼠中分析以下特定目标，这些小鼠自由进食并限制热量，这是一种已知可延缓运动神经元随年龄增长而丢失的策略。 具体目标1.采用FBT-PET定量后肢肌肉的神经支配。将测量下肢肌肉中的时间/活动曲线和三个实验组之间FBT摄取的差异。将通过MRI分析肌肉体积随老化的损失。将共同配准FBT-PET和MRI信号。通过测量以下指标分析信号特异性：（a）FBT血管清除率，（B）[3 H]FBT结合率，（c）[3 H] FBT放射自显影，（d）冷FBT/vesamicol对18 F-FBT摄取的阻断，和（e）VAChT敲低小鼠的FBT摄取。 具体目标2。分别使用特征良好的功能评估组合和单次肌力测量，在体内和体外检查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幅度和范围之间的关系。 具体目标3。使用体外测定定量小鼠肌肉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的多个部分中的转运蛋白的密度。IH信号特异性将通过用标记的α-银环蛇毒素双重染色来确定，所述标记的α-银环蛇毒素染色后末端AChR。 公共卫生相关性：肌肉去神经支配对肌肉减少症的作用仍然难以捉摸，特别是在人类中。验证FBT（氟苄基曲唑霉素）-正电子发射断层扫描（PET）作为一种新的，准确的，非侵入性的测量骨骼肌神经支配的啮齿动物将提供有价值的数据，可以迅速转化为一个有效的研究工具，在动物和人类。在临床上，它可用于评估干预措施，旨在预防和/或改善肌肉去神经支配的贡献，肌肉减少症和随后的身体残疾的老年人。该项目的结果旨在为获得监管批准所需的申请的准备和提交提供信息，以检查骨骼肌去神经及其对人类肌肉减少症的影响。在第二阶段，将放射性示踪剂FBT分配给其他机构将允许多中心评估其在量化与人类肌肉减少症相关的肌肉去神经支配中的效用。