Pathophysiological Interpretations of Dynamic PET/CT of Molecular Liver Biology

分子肝脏生物学动态 PET/CT 的病理生理学解释

• 批准号: 7284365
• 负责人: Susanne Keiding
• 金额: $ 16.25万
• 依托单位: AARHUS UNIVERSITY HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284365
• 关键词: Accounting; Aftercare; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Autoradiography; Benign; Bile fluid; Biliary; Binding; Biochemistry; Biology; Blood; Blood Vessels; Blood flow; Blood specimen; Buffers; Carbon Monoxide; Cholangiocarcinoma; Clinical; Clinical Management; Colorectal Cancer; Data; Defect; Detection; Development; Diagnosis; Diagnostic radiologic examination; Discontinuous Capillary; Equipment; Evaluation; Excretory function; Family suidae; Functional disorder; Galactose; Hemoglobin; Hepatic; Hepatic artery; Hepatocyte; Heterogeneity; Human; Impairment; Injury; Intervention; Invasive; Kinetics; Knowledge; Label; Lead; Ligands; Liver; Liver diseases; Liver neoplasms; Malignant - descriptor; Malignant Neoplasms; Measurement; Measures; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Liver; Methionine; Methodology; Methods; Microcirculation; Microscopic; Modeling; Molecular; Numbers; Obstructive Jaundice; Patients; Pharmaceutical Preparations; Phosphorylation; Physiological; Physiology; Portal vein structure; Positron-Emission Tomography; Primary biliary cirrhosis; Primary carcinoma of the liver cells; Procedures; Protein Biosynthesis; Proteins; Radiation therapy; Radio; Radiolabeled; Resolution; Severities; Surgical Portosystemic Shunt; Sus scrofa; Taurine Cholate; Technology; Testing; Time; Tissue Sample; Tissues; Today; Tracer; Translating; Translations; Transport Process; Verapamil; Vision; X-Ray Computed Tomography; analog; base; bench to bedside; bile duct; blood flow measurement; citrate carrier; clinically relevant; concept; data acquisition; design; galactokinase; human study; human subject; improved; intrahepatic; liver biopsy; liver metabolism; mathematical model; novel; primary sclerosing cholangitis; programs; radiotracer; research study; response; tumor

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.

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，以解释来自当代PET/CT的数据，并使用已建立的和新型PET示踪剂在肝脏患者的临床管理中实施这些模型。今天，肝脏多种功能的检查要么是非特异性的，要么是难以进行的.我们项目的总体目标是开发和实施动态PET/CT方法，这些方法可以显着提高我们对大量肝脏疾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）区域代谢和胆汁排泄的示踪动力学，以及5）通过动态高分辨率PET/CT检测肝脏疾病中的特定分子转运缺陷。设计和方法：一个实验室到床边的设计构成了这项研究。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。我们在猪的研究中测试，验证，挑战和完善这些模型，然后再转化为人类研究。用于确定示踪剂输入从门静脉和肝动脉（双输入功能）和肝脏微循环的模型进行了研究与11 CO-PET和对比CT在麻醉猪，验证与独立的侵入性程序，并受到挑战的流量和代谢的控制干预。然后，将精细的、统计上敏感的和特定的模型转化为非侵入性程序，用于人类（健康对照和患者）。研究了11 C-甲硫氨酸和18 FDGal作为测量总和局部肝脏代谢的合适放射性标记PET示踪剂。为了测量胆汁排泄功能，开发了新型示踪剂（11 C-RAL-01、11 C-维拉帕米、11 C-ICG和18 F-牛磺胆酸盐），并在人体试验之前在猪研究中进行了彻底试验。通过放射性HPLC分析肝活检（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建模。通过单示踪剂和双示踪剂放射自显影评价良性和恶性肝组织中示踪剂的显微分布。我们将创造新的，非侵入性的方法来测量血流和功能在肝脏使用敏感的PET/CT扫描。这将改善对大量肝病和肝癌患者的诊断和治疗。