18F Proline Preclinical PET Imaging In The Diagnosis of Early Stage Alcoholic Liver Fibrosis

18F 脯氨酸临床前 PET 成像在早期酒精性肝纤维化诊断中的应用

基本信息

批准号：
9242739
负责人：
Qi Cao
金额：
$ 19.05万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242739
关键词：
Alcoholic Liver Diseases Alcohols Animal Model Animals Biodistribution Biological Markers Cell physiology Cells Cicatrix Clinic Clinical Clinical Management Collagen Collagen Type I Culture Media Data Desmin Development Plans Diagnosis Diagnostic Diagnostic radiologic examination Discipline of Nuclear Medicine Doctor of Medicine Doctor of Philosophy Dose Early Diagnosis Early identification Endotoxins Enzyme-Linked Immunosorbent Assay Enzymes Fibroblasts Fibrosis Functional Imaging Glial Fibrillary Acidic Protein Goals Hepatic Hepatic Stellate Cell Hepatocyte Histopathology Image Imaging Techniques Immunoassay In Vitro Inbred BALB C Mice Interleukin-1 Receptors Investigation Label Link Liquid substance Liver Liver Fibrosis Liver diseases Maryland Measures Mentors Mitogen-Activated Protein Kinase Kinases Modeling Molecular Morphology Nuclear Organ Pathologic Patient Care Patients Positron-Emission Tomography Procedures Procollagen Production Proline Proteins Qi Reproducibility Research Research Personnel Role Sampling Serological Signal Pathway Signal Transduction Skeleton Staining method Stains Steatohepatitis System Techniques Technology Time Tissues Tracer Training Translating Universities Vimentin X-Ray Computed Tomography career development cell transformation clinical Diagnosis dosimetry experimental study feeding global health imaging study in vivo liver injury mRNA Expression medical schools molecular imaging mouse model noninvasive diagnosis pre-clinical problem drinker professor protein activation radiotracer receptor skeletal technique development uptake

项目摘要

This K08 application is submitted by Qi Cao, M.D., Ph.D., Assistant Professor of Diagnostic Radiology and Nuclear Medicine at the University of Maryland School of Medicine. My long term goal is to become an independent investigator focusing on establishing a reliable and reproducible PET/CT technique to noninvasively and specifically diagnose early-stage alcoholic liver fibrosis (ALF). Toward this goal, I propose a mentored career development plan which provides the following training in: 1) preclinical experiments to assess specific cellular tracer uptake in vitro, 2) in new radiotracer synthesis and preclinical imaging in order to quantify biodistribution and dosimetry, and 3) in functional molecular imaging for the diagnosis of early stage liver fibrosis. SPECIFIC AIMS: The first aim is to evaluate the role of proline in collagen synthesis using 3H-labeled proline in an in vitro culture system of hepatic stellate cells (HSCs) isolated from livers of animals with alcoholic steatosis (AS), alcoholic steatohepatitis (ASH), early stage alcoholic liver fibrosis (EAF), and late stage alcoholic liver fibrosis (LAF) by using beta counting. The second aim is to establish dynamic 18F-proline PET imaging to assess radiotracer biodistribution in 12 critical organs/tissues and to optimize dosing and timing conditions which will translate this procedure to image ALF in animals with AS, ASH, EAF, and LAF as described in Aim 3. The third aim is to study the role of 18F-proline in the diagnosis of early-stage liver fibrosis in HSC from animals with AS, ASH, EAF, and LAF by static 18F-proline PET/CT imaging. The proposed complementary approaches in the specific aims will help to: (1) establish important parameters of 18F-proline labeling by optimizing tracer dosing and imaging timing conditions; and (2) determine the experimental importance of 18F-proline in the assessment of collagen production in in vitro (aim 1) and in vivo (aims 2 and 3) models, which will provide a new means to assess early liver fibrosis in patients with ALD. This line of investigation will use functional imaging to fill critical gaps in the mechanism of in vivo collagen production, which will further our understanding of liver disease and advance clinic treatment by providing a noninvasive means to diagnose early-stage liver fibrosis at a stage before damage becomes permanent. Through intensive training in the application of non-invasive molecular imaging to ALD, I will gain the expertise required of an independent investigator to apply molecular imaging to the study and diagnosis of liver disease. RELEVANCE: The project will use noninvasive 18F-proline PET/CT imaging to correlate radiotracer incorporation activity within scar formation cells with scar collagen formation. The ability to image scar formation will provide valuable data to enable the development of this technique for noninvasive identification of early-stage liver disease during routine patient care, which will greatly advance the treatment of liver disease.

本 K08 申请由诊断放射学助理教授、医学博士、哲学博士曹奇提交，马里兰大学医学院的核医学。我的长期目标是成为独立研究者致力于建立可靠且可重复的 PET/CT 技术无创且特异性地诊断早期酒精性肝纤维化（ALF）。为了这个目标，我提出一个指导性职业发展计划提供以下培训：1) 临床前实验评估体外特定细胞示踪剂的摄取，2) 在新的放射性示踪剂合成和临床前成像中，以便量化生物分布和剂量测定，以及 3) 用于早期诊断的功能分子成像肝纤维化。具体目标：第一个目标是使用 3H 标记的脯氨酸评估脯氨酸在胶原蛋白合成中的作用在从酒精动物肝脏中分离出的肝星状细胞 (HSC) 的体外培养系统中脂肪变性（AS）、酒精性脂肪性肝炎（ASH）、早期酒精性肝纤维化（EAF）和晚期使用 β 计数检测酒精性肝纤维化 (LAF)。第二个目标是建立动态18F-脯氨酸PET 通过成像评估放射性示踪剂在 12 个关键器官/组织中的生物分布并优化剂量和时间安排将此程序转化为具有 AS、ASH、EAF 和 LAF 的动物中 ALF 成像的条件目标3中描述。第三个目标是研究18F-脯氨酸在诊断早期肝纤维化中的作用通过静态 18F-脯氨酸 PET/CT 成像，检测患有 AS、ASH、EAF 和 LAF 的动物的 HSC。针对具体目标提出的补充方法将有助于：（1）建立重要参数通过优化示踪剂剂量和成像计时条件进行 18F-脯氨酸标记； (2) 确定 18F-脯氨酸在评估体外（目标 1）和体内胶原蛋白生成中的实验重要性（目标 2 和 3）模型，这将为评估 ALD 患者早期肝纤维化提供新方法。这研究线将使用功能成像来填补体内胶原蛋白机制的关键空白生产，这将加深我们对肝病的了解并通过提供在损害成为永久性之前阶段诊断早期肝纤维化的无创方法。通过非侵入性分子成像在 ALD 中的应用的强化培训，我将获得专业知识独立研究者需要将分子成像应用于肝病的研究和诊断。相关性：该项目将使用无创 18F-脯氨酸 PET/CT 成像来关联放射性示踪剂疤痕形成细胞内的掺入活性与疤痕胶原蛋白的形成。疤痕成像能力形成将为非侵入性识别技术的开发提供有价值的数据在常规患者护理过程中发现早期肝病，这将极大地推进肝病的治疗。