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）：此项目响应RFA-DA-001。它的目标是扩展正电子发射断层扫描（PET）flurobenzyltrozamicol（FBT）放射性物体在大脑研究中的实用性，并扩展到骨骼肌衰老的研究中。越来越多的证据支持骨骼肌的慢性，与年龄相关的结构和功能下降中神经变性的作用。它将检验以下假设：无创成像程序FBT-PET可用于评估啮齿动物整个衰老过程中的骨骼肌神经。结果将为其在人类肌肉减少症中的作用提供分析。 将在年轻人（7个月）和年龄（24个月）的小鼠中分析以下特定目标，并备用卡路里限制，这是一种随着老化而延迟运动神经元损失的动作。 特定目标1。使用FBT-PET量化后肢肌肉神经。将测量下后肢肌肉的时间/活性曲线和三个实验组之间FBT吸收的差异。 MRI将分析随着衰老的肌肉体积损失。 FBT-PET和MRI信号将共同注册。信号特异性将通过测量进行分析：（a）FBT血管清除率，（b）[3H] FBT结合，（c）[3H] FBTAUTURADICONGE，（d）通过VACHT敲门鼠标限制冷FBT/VESAMICOL和（e）FBT摄入的18F-FBT吸收。 具体目的2。分别使用特征良好的功能评估电池和单个肌肉力量测量来检查体内FBT-PET和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神经神经的大小和扩展之间的关系。 特定目标3。使用体外确定来量化小鼠肌肉vacht密度，并与FBT-PET建立关系。 VACHT的免疫组织化学（IH）将使我们能够在多个纵向肌肉的多个部分中测量转运蛋白的密度。 IH信号特异性将通过用标记为A-bungarotoxin的标记为末端ACHR的A-Bungarotoxin进行双重染色来确定。 公共卫生相关性：肌肉神经对肌肉减少症的贡献仍然难以捉摸，尤其是在人类中。 FBT（Flurobenzyltrozamicol） - 峰值发射断层扫描（PET）的验证是一种新颖，准确，无创的啮齿动物骨骼肌神经支配的测量，将提供有价值的数据，可以快速转化为动物和人类中有效的研究工具。在临床上，它可用于评估旨在预防和/或改善肌肉神经支配对肌肉减少症的贡献以及随后在老年人中的身体残疾的贡献。该项目的结果旨在为获得监管批准所必需的申请的准备和提交，以检查骨骼肌肉神经膜及其对人类肌肉减少症的影响。在第二阶段，放射性示意剂FBT向其他机构的分布将允许对其在量化与人类肌肉减少症相关的肌肉修神经方面进行多中心评估。