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的数学模型来解释来自当代PET/CT的数据，并使用已建立的和新型的PET示踪剂在肝脏患者的临床管理中实施这些模型。今天，对肝脏多种功能的检查不是非特异性的，就是难以执行。我们计划的总体目标是开发和实施动态PET/CT方法，以显著提高我们对大群肝病患者肝脏代谢紊乱的了解。具体目标是：1)肝脏双输入功能的非侵入性测定，2)肝脏微循环，3)肝动脉缓冲反应，4)局部代谢和胆汁排泄的示踪动力学，5)动态高分辨率PET/CT检测肝脏疾病中的特异性分子运输缺陷。设计和方法：本研究采用床到床设计。基于肝脏生理学、病理生理学和生化的知识，我们创建了适用于动态PET/CT的新的数学模型。我们在将这些模型转化为人体研究之前，在猪的研究中测试、验证、挑战和改进这些模型。在麻醉猪中，用11个CO-PET和对比CT研究了确定来自门静脉和肝动脉(双输入功能)和肝脏微循环的示踪剂输入的模型，并用独立的侵入性程序进行了验证，并通过对血流和代谢的控制干预进行了挑战。然后，精炼的、统计上敏感的和特定的模型被转化为对人类(健康对照和患者)的非侵入性程序。~(11)C-蛋氨酸和~(18)FDGal是测量肝脏总代谢和局部代谢的合适的放射性标记PET示踪剂。为了测量胆汁排泄功能，开发了新的示踪剂(11C-RAL-01，11C-维拉帕米，11C-ICG和18F-牛磺胆酸盐)，并在猪研究中进行了彻底的测试，然后在人体上进行了测试。对肝脏活检组织(猪)和血液样本(猪和人)进行了放射性高效液相分析，以确定放射性标记代谢物的时间进程，并优化示踪剂代谢的动力学模型。用单、双示踪剂放射自显影技术评价良性和恶性肝组织中示踪剂的微观分布。我们将创造新的、非侵入性的方法，使用灵敏的PET/CT扫描来测量肝脏的血流和功能。这将改善对大批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.