KINETICS OF MUSCLE METABOLISM BY POSITRON TRACERS

正电子示踪剂的肌肉代谢动力学

• 批准号: 3361605
• 负责人: HEINRICH TAEGTMEYER
• 金额: $ 23.74万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3361605
• 关键词: bioenergetics; brain metabolism; chemical reaction; diabetes mellitus; enzyme substrate; extracellular; glucose metabolism; glucose transport; heart contraction; heart metabolism; insulin; isolation perfusion; laboratory rabbit; laboratory rat; mathematical model; myocardial ischemia /hypoxia; neoplasm /cancer radiodiagnosis; peripheral blood vessel disorder; phosphorylation; positron emission tomography; radiopharmacology; reperfusion

Positron emission tomography (PET) of regional blood flow and metabolism in heart, brain and neoplastic tissue has introduced a new class of tracers to record cellular events in intact, functioning organs without destruction of the tissue. At the present time, further development of the PET technique is hampered by its semi-quantitative nature. The broad objective of this project is to exploit the unique characteristics of positron emitting isotopes for the quantitative study of muscle metabolism and for the correlation between metabolism and function in vivo. Prior experiments have demonstrated the utility of the glucose analog [18F]-2-deoxy-2-fluoro-D-glucose (FDG) for the rapid kinetic analysis of glucose uptake by heart and skeletal muscle as it relates to organ function, but the technique requires further validation. Radioactivity in the tissue is measured together with the FDG input function on a second-by-second basis. This technique not only provides reliable data for kinetic modeling, but also a means to test the hypothesis that there is a feedback system to match work and substrate C3 utilization on a beat-to-beat time scale. The isolated working rat heart will be used to correlate the kinetics of tracer uptake with direct measurements of the rate of glucose utilization under control conditions and after specific perturbations including competing substrates, stimulation of glucose transport by insulin, and ischemia/reperfusion. In vivo application of the technique to skeletal muscle will utilize the rabbit hindlimb under control conditions and during euglycemic/hyperinsulinemic clamps or during periods of increased contractile activity. For both hearts and skeletal muscle, differences in the kinetics of the analog and glucose in terms of intracellular phosphorylation and dephosphorylation will be assessed by direct biochemical measurements of the Km and Vmax of hexokinase and glucose 6-phosphatase for glucose and FDG. These analyses seek direct evidence for changes in key components of the correction factor relating tracer to tracee (lumped constant). Measurements of enzyme activities and intracellular metabolite levels will be used to assess the validity of the kinetic analyses. It is expected that we will obtain quantitative data on glucose metabolism in vivo which, in turn, provide critical information on the action of insulin in muscle as well as substrate metabolism and parameters of tissue viability on reperfusion of ischemic myocardium.

局部血流和代谢的正电子发射断层扫描 (PET) 在心脏、大脑和肿瘤组织中引入了一类新的示踪剂 在不破坏的情况下记录完整、功能正常的器官中的细胞事件 的组织。目前，PET的进一步发展 该技术因其半定量性质而受到阻碍。广泛的目标 该项目的目的是利用正电子的独特特性 发射同位素用于肌肉代谢的定量研究和 体内代谢与功能的相关性。先前的实验 已经证明了葡萄糖类似物的效用 [18F]-2-脱氧-2-氟-D-葡萄糖 (FDG) 用于快速动力学分析 心脏和骨骼肌对葡萄糖的摄取，因为它与器官有关 功能，但该技术需要进一步验证。放射性 组织与 FDG 输入功能一起在 逐秒为基础。该技术不仅提供了可靠的数据 动力学建模，也是检验存在假设的一种方法 反馈系统，以匹配工作和底物 C3 利用率 逐次心跳的时间刻度。离体工作大鼠心脏将用于 将示踪剂摄取的动力学与直接测量相关联 控制条件下和特定后的葡萄糖利用率 干扰包括竞争底物、葡萄糖刺激 胰岛素转运和缺血/再灌注。体内应用 骨骼肌技术将利用兔子后肢进行控制 状况以及正常血糖/高胰岛素钳夹期间或经期期间 收缩活动增加。对于心脏和骨骼肌来说， 类似物和葡萄糖的动力学差异 细胞内磷酸化和去磷酸化将通过以下方式评估 直接生化测量己糖激酶的 Km 和 Vmax 葡萄糖6-磷酸酶用于葡萄糖和FDG。这些分析寻求直接 相关修正系数关键组成部分变化的证据 示踪剂到被追踪者（集总常数）。酶活性的测量和 细胞内代谢物水平将用于评估该方法的有效性 动力学分析。预计我们将获得定量数据 体内葡萄糖代谢，反过来又提供了关键信息 胰岛素在肌肉中的作用以及底物代谢和 缺血心肌再灌注时组织活力的参数。