Pathophysiological Interpretations of Dynamic PET/CT of Molecular Liver Biology

描述（由申请人提供）：该计划的愿景是创建基于生理学的数学模型来解释来自当代PET/CT的数据，并将这些模型应用于使用已建立和新型PET示踪剂的肝脏患者的临床管理中。目前，对肝脏多种功能的检查要么是非特异性的，要么很难进行。我们项目的总体目标是开发和实施动态PET/CT方法，这些方法可以显著提高我们对大量肝病患者肝脏代谢紊乱的理解。具体目标是1)无创测定肝脏双输入功能，2)肝脏微循环，3)肝动脉缓冲反应，4)区域代谢和胆汁排泄的示踪动力学，5)动态，高分辨率PET/CT检测肝脏疾病的特异性分子运输缺陷。设计与方法：本研究采用从床到床的设计。基于肝脏生理学、病理生理学和生物化学的知识，我们创建了适用于动态PET/CT的新数学模型。在转化为人类研究之前，我们在猪研究中测试、验证、挑战和完善这些模型。通过11个CO-PET和对比ct对麻醉猪门静脉和肝动脉（双输入功能）和肝脏微循环的示踪剂输入模型进行了研究，并通过独立的侵入程序进行了验证，并通过流量和代谢的控制干预进行了挑战。这些精确的、统计上敏感的和特定的模型随后被转化为非侵入性的程序，用于人类（健康对照者和患者）。研究了11c -蛋氨酸和18FDGal作为合适的放射性标记PET示踪剂用于测量总肝脏代谢和局部肝脏代谢。为了测量胆汁排泄功能，研究人员开发了新型示踪剂（11C-RAL-01、11c -维拉帕米、11C-ICG和18f -牛磺胆酸盐），并在猪实验中进行了彻底测试，然后再进行人体试验。采用放射性高效液相色谱法分析肝脏活检（猪）和血液样本（猪和人），以确定放射性标记代谢物的时间过程，并优化示踪剂代谢的动力学模型。示踪剂在良性和恶性肝组织的显微分布是评价单和双示踪剂放射自显影。我们将创造新的、无创的方法来测量血液流动和肝脏功能，使用敏感的PET/CT扫描。这将改善对大量肝病和肝癌患者的诊断和治疗。

DESCRIPTION (provided by applicant): The vision of the program is to create physiologically based mathematical models to interpret data from contemporary PET/CT and to implement these models in the clinical management of liver patients using established and novel PET-tracers. Today, examinations of the livers multiple functions are either non- specific or difficult to perform. The overall aim of our program is to develop and implement dynamic PET/CT methods that can significantly improve our understanding of the disturbed liver metabolism in the large groups of patients suffering from liver disease. Specific aims are 1) non-invasive determination of hepatic dual input function, 2) liver microcirculation, 3) hepatic arterial buffer response, 4) tracer kinetics of regional metabolism and biliary excretion, and 5) specific molecular transport defects in liver diseases detected by dynamic, high resolution PET/CT. Design and Methods: A bench-to-bedside design constitutes the study. Based on knowledge of liver physiology, pathophysiology, and biochemistry we create new mathematical models applicable to dynamic PET/CT. We test, validate, challenge, and refine these models in pig studies before translation into human studies. Models for determining tracer input from the portal vein and the hepatic artery (dual input function) and microcirculation of the liver are investigated with 11 CO-PET and contrast-CT in anaesthetized pigs, validated with independent invasive procedures, and challenged by controlled interventions of the flow and metabolism. The refined, statistically sensitive and specific models are then translated as non-invasive procedures into humans (healthy controls and patients). 11C-Methionine and 18FDGal are investigated as suitable radio-labeled PET tracers for measuring the total and regional hepatic metabolism. To measure biliary excretory function, novel tracers (11C-RAL-01,11 C-verapamil, 11C-ICG and 18F-taurocholate) are developed and tested thoroughly in pig studies before tested in humans. Liver biopsies (pigs) and blood samples (pigs and humans) are analyzed by radio-HPLC to determine the time course of radio-labeled metabolites and to optimize kinetic modeling of tracer metabolism. The microscopic distribution of tracers in benign and malignant liver tissue is evaluated by single- and dual-tracer autoradiography. We will create new, non-invasive methods for measuring blood flow and function in the liver using sensitive PET/CT scanning. This will lead to improved diagnosis and treatment of the large groups of patients with liver disease and cancer in the liver.