Hyperpolarized 13C Metabolic Imaging of Tumorigenesis in the Liver

肝脏肿瘤发生的超极化 13C 代谢成像

• 批准号: 10727760
• 负责人: Kelvin L Billingsley
• 金额: $ 46.18万
• 依托单位: LOYOLA UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727760
• 关键词: Anatomy; Automobile Driving; Biochemical Reaction; Bioenergetics; Biological Assay; Biological Markers; Cancer Etiology; Cancerous; Cell Survival; Cessation of life; Characteristics; Chronic; Clinical; Development; Diagnosis; Diagnostic; Diethylnitrosamine; Disease; Disease Progression; Early Diagnosis; Emerging Technologies; Energy Metabolism; Enzymes; Epidemic; Fibrosis; Functional disorder; Generations; Glycolysis; Goals; Guidelines; HepG2; Hepatic; Hepatitis Viruses; Hepatocarcinogenesis; Hepatocyte; Histology; Image; In Vitro; Incidence; Inflammation; Interdisciplinary Study; Intravenous; Investigation; Isotope Labeling; Kinetics; Label; Libraries; Liver; Liver diseases; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurement; Measures; Medical Imaging; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Modeling; Monitor; Morphology; Obesity; Onset of illness; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phosphoenolpyruvate; Physical assessment; Play; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Prognosis; Property; Pyruvate; Pyruvate Kinase; Rattus; Reaction; Relaxation; Reporting; Research; Risk; Role; Sampling Errors; Series; Signal Transduction; Staging; Survival Rate; Technology; Testing; Time; Tissues; Toxic effect; cancer diagnosis; chemical property; chemotherapy; clinical translation; clinically significant; cytotoxicity; design; experimental study; high risk population; imaging biomarker; imaging modality; improved; in vivo; in vivo evaluation; in vivo imaging; innovation; interest; liver biopsy; liver metabolism; metabolic imaging; metabolic phenotype; non-invasive monitor; noninvasive diagnosis; novel; novel therapeutics; physical property; prevent; real-time images; scaffold; tool; tumor; tumor microenvironment; tumorigenesis

Project Summary. Aberrant glycolysis and mitochondrial function are features of most liver diseases including hepatocellular carcinoma (HCC). Despite these metabolic signatures, the absence of methods to noninvasively assess metabolic fluxes in vivo limits the accurate characterization of liver diseases and in turn impedes the development of new therapies. In the proposed study, we will employ novel hyperpolarized (HP) 13C probes to image glycolysis, a pathway that plays a critical role in HCC onset and progression. Importantly, our cross-disciplinary research team has made significant advancements in the design and application of HP 13C-glycerate probes. We have demonstrated that HP [1-13C]glycerate is a non-toxic substrate with a long T1 relaxation time (60 sec), and this HP probe is sensitive to alterations in liver metabolism in vivo, offering inroads for clinical translation. In addition, our recent studies in HCC (diethylnitrosamine [DEN]-induced rat model) demonstrated that HP [1- 13C]glycerate can successfully distinguish HCC from healthy liver based upon the unique metabolic fluxes detected in the cancerous tissue. Given these advancements, we now propose that the HP 13C-glycerate scaffold can be systematically optimized to yield 2nd generation HP probes, which provide highly sensitive analyses of enzymatic reactions in the liver and diagnostic assessments of abnormal fluxes in HCC. The overarching goal of the proposed project is to use the HP 13C-glycerate technology to establish in vivo imaging biomarkers for assessing altered metabolism during HCC development. To this end, in Aim 1, we will synthesize a focused library of 2nd generation 13C-glycerate probes that are specifically designed to increase the metabolic information obtained from HP experiments. In Aim 2, we will analyze the physicochemical properties of these probes in order to determine top agents to advance towards in vivo HP studies. In Aim 3, we will initially establish imaging biomarkers for HP 13C-glycerates in the DEN rat model and identify specific probes that provide clear metrics for distinguishing HCC. These 13C-glycerate probes will then be used to evaluate a stepwise progression from normal liver to HCC in the DEN model. Four pathological states will be examined: baseline, chronic inflammation, fibrosis, and HCC. In vivo metrics for glycolysis will be compared among the states, and these results will be validated with tissue analyses. Overall, the proposed studies offer an innovative strategy for tackling a challenge of clinical significance. State-of-the-art HP probes will be used to assess altered glycolysis in hepatocarcinogenesis. This technology will in turn provide specific in vivo biomarkers that represent the metabolic pathways of interest in HCC, providing a noninvasive method for assessing disease progression in at- risk patients.

项目摘要。 异常的糖酵解和线粒体功能是大多数肝脏疾病（包括肝细胞）的特征 癌（HCC）。尽管有这些代谢特征，但缺乏非侵入性评估的方法 体内代谢通量限制了肝病的准确表征，进而阻碍了发展 新疗法。在拟议的研究中，我们将采用新型超极化（HP）13C探针进行图像 糖酵解，在HCC发作和进展中起关键作用的途径。重要的是，我们的跨学科 研究团队在HP 13C甘油探针的设计和应用方面取得了重大进步。 我们已经证明了HP [1-13C]甘油酸是一种无毒的底物，其T1松弛时间（60秒）， 该HP探针对体内肝脏代谢的改变敏感，为临床翻译提供了进口。在 此外，我们最近在HCC（二乙基硝基胺[DEN]诱导的大鼠模型）的研究表明HP [1- 13C]甘油酸可以根据独特的代谢通量成功将HCC与健康肝脏区分开 在癌组织中检测到。鉴于这些进步，我们现在建议HP 13C-甘油 可以系统地优化脚手架以产生第二代HP探针，这些探针提供了高度敏感的 肝脏中酶促反应的分析和HCC异常通量的诊断评估。这 拟议项目的总体目标是使用HP 13C甘油技术来建立体内成像 评估HCC开发过程中新陈代谢改变的生物标志物。为此，在AIM 1中，我们将合成 第二代13C-甘油探针的重点库，专门设计用于增加代谢 从HP实验获得的信息。在AIM 2中，我们将分析这些物理化学特性 探针以确定顶级代理，以迈向体内HP研究。在AIM 3中，我们最初将建立 成像DEN大鼠模型中HP 13C-甘油甘油的生物标志物，并确定提供清晰的特定探针 区分HCC的指标。然后，这些13C-甘油探针将用于评估逐步进程 在DEN模型中从正常肝脏到HCC。将检查四个病理状态：基线，慢性 炎症，纤维化和HCC。在各州之间将比较用于糖酵解的体内指标，这些指标将 结果将通过组织分析验证。总体而言，拟议的研究为 应对临床意义的挑战。最先进的HP探针将用于评估改变的糖酵解 在肝癌发生中。这项技术反过来将提供特定的体内生物标志物，代表 HCC中感兴趣的代谢途径，提供了一种无创方法来评估AT-的疾病进展 风险患者。