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

本K 08申请由Qi Cao，M.D.提交，哲学博士、放射诊断学助理教授， 核医学在马里兰州医学院。我的长期目标是成为一名 独立研究者，专注于建立可靠和可重复的PET/CT技术， 非侵入性和特异性诊断早期酒精性肝纤维化（ALF）。为了实现这一目标，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， 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， 定量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 具体目的：第一个目的是使用3 H标记的脯氨酸评价脯氨酸在胶原合成中的作用 在从酒精中毒动物肝脏分离的肝星状细胞（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）和晚期酒精性肝纤维化（EAF）。 酒精性肝纤维化（LAF），使用β计数。第二个目标是建立动态18F-脯氨酸PET 成像，以评估12个关键器官/组织中的放射性示踪剂生物分布，并优化给药和时间 将该程序转化为AS、ASH、EAF和LAF动物中ALF成像的条件， 目标3中描述的。第三个目的是研究18F-脯氨酸在早期肝纤维化诊断中的作用 通过静态18F-脯氨酸PET/CT成像，在患有AS、ASH、EAF和LAF的动物的HSC中。 在具体目标中提出的补充办法将有助于：（1）确定重要参数 通过优化示踪剂剂量和成像时间条件来确定18F-脯氨酸标记的最佳剂量;以及（2）确定18F-脯氨酸标记的最佳剂量。 18F-脯氨酸在体外（目的1）和体内胶原蛋白生成评估中的实验重要性 (aims 2和3）模型，这将提供一个新的手段来评估早期肝纤维化患者与ALD。这 一系列的研究将使用功能成像来填补体内胶原机制的关键空白， 生产，这将进一步加深我们对肝脏疾病的认识，并通过提供一个先进的临床治疗， 非侵入性手段，以诊断早期肝纤维化的阶段之前，损害成为永久性的。 通过强化培训，在ALD的非侵入性分子成像的应用，我将获得专业知识， 需要独立的研究者将分子成像应用于肝脏疾病的研究和诊断。 相关性：该项目将使用无创18 F-脯氨酸PET/CT成像， 在瘢痕形成细胞内的掺入活性与瘢痕胶原形成。对疤痕的成像能力 形成将提供有价值的数据，使这种技术的发展，非侵入性识别 在常规患者护理过程中，早期肝病的发生率将大大提高，这将大大推进肝病的治疗。

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.