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: 10223967
• 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/10223967
• 关键词: 3-Dimensional; Alcoholic Liver Diseases; Alcoholic steatohepatitis; 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 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; 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; Serology; Signal Pathway; Signal Transduction; Skeleton; Stains; System; TLR1 gene; 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; interleukin-1 receptor-associated kinase; liver injury; mRNA Expression; medical schools; molecular imaging; mouse model; noninvasive diagnosis; pre-clinical; preclinical imaging; problem drinker; professor; protein activation; radiotracer; 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.

本K08申请书由放射学诊断助理教授、医学博士曹琦提交。 马里兰大学医学院的核医学。我的长期目标是成为一名 独立研究人员，专注于建立可靠和可重复性的PET/CT技术 无创性、特异性地诊断早期酒精性肝纤维化(ALF)。为了实现这一目标，我建议 有指导的职业发展计划，提供以下方面的培训：1)临床前实验 评估体外特异性细胞示踪剂摄取，2)在新的放射性示踪剂合成和临床前成像中，以便 量化生物分布和剂量学；3)功能分子成像早期诊断 肝纤维化。 具体目标：第一个目标是用~3H标记的Pro来评价Pro在胶原合成中的作用 酒精中毒动物肝脏星状细胞体外培养体系的建立 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 用β计数法检测酒精性肝纤维化(LAF)。第二个目标是建立动态18F-Pro-PET 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机的成像 将此过程转换为AS、ASH、EAF和LAF为AS的动物ALF的条件 第三个目的是研究18F-Pro在早期肝纤维化诊断中的作用 在AS、ASH、EAF和LAF动物的HSC中进行静态18F-Proline PET/CT成像。 在具体目标方面拟议的补充办法将有助于：(1)确定重要的参数 通过优化示踪剂剂量和成像定时条件来进行18F-Pro标记；(2)确定 18F-Pro在评价体外和体内胶原生成中的实验意义(目标1) (AIMS 2和3)模型，这将为评估ALD患者的早期肝纤维化提供一种新的手段。这 一系列研究将使用功能成像来填补体内胶原蛋白机制的关键空白 这将加深我们对肝脏疾病的了解，并通过提供一种 非侵入性意味着在肝损伤成为永久性损伤之前的某个阶段诊断早期肝纤维化。 通过在ALD中应用非侵入性分子成像的强化培训，我将获得专业知识 需要独立的研究人员将分子成像应用于肝脏疾病的研究和诊断。 相关性：该项目将使用非侵入性18F-Proline PET/CT成像来关联放射性示踪剂 随着瘢痕胶原的形成，瘢痕形成细胞内的掺入活性。对疤痕进行成像的能力 地层将提供宝贵的数据，使这种非侵入性识别技术的发展成为可能 在常规的患者护理中，早期肝病的发病率将大大提高，这将大大促进肝病的治疗。

项目成果

Quantification of Hepatic Lipid Using 7.0T Proton Magnetic Resonance Spectroscopy and Computed Tomography in Mild Alcoholic Steatotic Mice.

使用 7.0T 质子磁共振波谱和计算机断层扫描对轻度酒精性脂肪变性小鼠的肝脂质进行定量。

• DOI: 10.4172/2167-0889.1000234
• 发表时间: 2018
• 期刊: Journal of liver
• 作者: Cao,Qi;Xu,Su;Li,Shujing;Chen,Minjie;Sun,Xicui;Wan,Yamin;Pi,Liya;Ying,Zhekang;Ren,Bin
• 通讯作者: Ren,Bin