Hyperpolarized 13C Metabolic Imaging of Tumorigenesis in the Liver

肝脏肿瘤发生的超极化 13C 代谢成像

基本信息

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
项目类别：
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

项目摘要

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。糖酵解和线粒体功能异常是大多数肝脏疾病（包括肝细胞疾病）的特征癌（HCC）。尽管有这些代谢特征，但缺乏非侵入性评估方法体内代谢通量限制了肝脏疾病的准确表征，进而阻碍了肝脏疾病的发展的新疗法。在拟议的研究中，我们将采用新型超极化（HP）13C 探针来成像糖酵解，一种在 HCC 发病和进展中发挥关键作用的途径。重要的是，我们的跨学科研究团队在HP 13C-甘油酸探针的设计和应用方面取得了重大进展。我们已经证明HP [1-13C]甘油酸是一种无毒底物，具有较长的T1弛豫时间（60秒），这种 HP 探针对体内肝脏代谢的变化敏感，为临床转化提供了进展。在此外，我们最近对 HCC（二乙基亚硝胺 [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区分 HCC 和健康肝脏在癌组织中检测到。鉴于这些进步，我们现在建议 HP 13C-甘油酸酯可以系统地优化支架以产生第二代 HP 探针，该探针提供高灵敏度肝脏酶反应分析和 HCC 异常通量诊断评估。这该项目的总体目标是使用 HP 13C-甘油酸技术建立体内成像用于评估 HCC 发展过程中代谢变化的生物标志物。为此，在目标 1 中，我们将综合第二代 13C-甘油酸探针的重点库，专门设计用于增加代谢从 HP 实验中获得的信息。在目标 2 中，我们将分析这些物质的理化特性探针以确定最佳药物以推进体内 HP 研究。在目标 3 中，我们将首先建立对 DEN 大鼠模型中 HP 13C-甘油的生物标志物进行成像，并识别可提供清晰的特异性探针区分 HCC 的指标。这些 13C-甘油酸探针将用于评估逐步进展 DEN 模型中从正常肝脏到肝癌。将检查四种病理状态：基线、慢性炎症、纤维化和肝癌。糖酵解的体内指标将在各州之间进行比较，这些结果将通过组织分析进行验证。总体而言，拟议的研究提供了一种创新策略应对具有临床意义的挑战。最先进的 HP 探针将用于评估糖酵解的改变在肝癌发生过程中。该技术将反过来提供代表特定体内生物标志物 HCC 中感兴趣的代谢途径，为评估 at- 疾病进展提供了一种非侵入性方法风险患者。