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

• 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
• 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

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.

该K08申请由M.D. 马里兰大学医学院的核医学。我的长期目标是成为一个 专注于建立可靠且可再现的PET/CT技术的独立研究者 非侵入性，专门诊断早期酒精性肝纤维化（ALF）。朝着这个目标，我提出了一个 指导的职业发展计划提供以下培训：1）临床前实验 在体外评估特定的细胞示踪剂摄取，2）在新的放射性示踪剂合成和临床前成像中，以便为了 量化生物分布和剂量法，3）在功能分子成像中进行早期诊断 肝纤维化。 具体目的：第一个目的是使用3H标记的脯氨酸评估脯氨酸在胶原蛋白合成中的作用 在从含酒精的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），早期酒精肝纤维化（EAF）和晚期 通过使用Beta计数，酒精性肝纤维化（LAF）。第二个目的是建立动态18F-饮宠物 成像评估12个关键器官/组织中的放射性示意剂生物分布并优化给药和计时 将此过程转化为AS，As，Ash，EAF和LAF的动物中ALF的条件 在AIM 3中描述。第三个目的是研究18F-殖民地在诊断早期肝纤维化诊断中的作用 在HSC中，由AS，AS，ASH，EAF和LAF的动物进行静态18F-宠物/CT成像。 特定目的中提出的互补方法将有助于：（1）建立重要参数 通过优化示踪剂剂量和成像时间条件来进行18F-丙烯的标记； （2）确定 在体外评估胶原蛋白产生（AIM 1）和体内的胶原蛋白产生中的实验重要性 （目标2和3）模型，该模型将提供一种新的手段来评估ALD患者的早期肝纤维化。这 调查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，这将进一步了解肝病，并通过提供诊所治疗 在损害永久性之前，在阶段诊断早期肝纤维化的无创手段。 通过将非侵入性分子成像应用于ALD的密集培训，我将获得专业知识 独立研究者要求将分子成像应用于肝病的研究和诊断。 相关性：该项目将使用非侵入性18F-丙烯PET/CT成像与radiotracer相关 与疤痕胶原形成的疤痕形成细胞中融合活性。图像疤痕的能力 编队将提供有价值的数据，以使该技术的开发用于非侵入性识别 常规患者护理期间的早期肝病，这将大大推动肝病的治疗。