Novel hyperpolarized 13C molecular imaging techniques for differentiating NAFLD and NASH

用于区分 NAFLD 和 NASH 的新型超极化 13C 分子成像技术

• 批准号: 10240628
• 负责人: Michael Ohliger
• 金额: $ 41.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240628
• 关键词: Address; Alanine; Biochemical; Biological Assay; Biopsy; Breathing; Calibration; Cardiovascular Diseases; Characteristics; Cirrhosis; Clinical; Clinical Management; Clinical Markers; Complex; Diagnosis; Dihydroxyacetone; Disease; Disease Marker; Disease Progression; Echo-Planar Imaging; Energy Metabolism; Fatty Liver; Goals; Gold; Grant; Hepatic; High Fat Diet; Human; Human Volunteers; Image; Imaging Techniques; Imaging technology; Inflammation; International; Lipids; Liver; Liver diseases; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Manganese; Measures; Metabolic; Metabolism; Methods; Modeling; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathology; Patients; Physiologic pulse; Positioning Attribute; Pre-Clinical Model; Pyruvate; RF coil; Rattus; Research Project Grants; Rodent Model; Sampling Errors; Site; System; Testing; Time; Tissue Sample; Translations; base; cancer transplantation; clinical translation; diabetic; high risk; human imaging; image reconstruction; imaging approach; imaging biomarker; imaging modality; imaging probe; improved; liver biopsy; liver imaging; liver metabolism; liver transplantation; metabolic imaging; molecular imaging; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel diagnostics; novel strategies; public health relevance; radio frequency; respiratory; response; standard measure; tool; treatment response

PROJECT SUMMARY / ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition characterized by ectopic hepatic lipid accumulation in association with obesity and type 2 diabetes. A progressive derangement of hepatic energy metabolism underlies the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH), a condition that carries high risk for progression to critical liver disease states. Unfortunately, the current method for monitoring NAFLD is liver biopsy, which has major limitations especially its high degree of invasiveness. Hyperpolarized 13C magnetic resonance imaging (MRI) is an emerging molecular imaging modality with a unique capability to access intermediary energy metabolism in a non-invasive manner, which is currently undergoing translation into human studies at several sites internationally in studies of cancer and cardiovascular disease. The goal of this new R01 project is to investigate a new application of this new molecular imaging modality to the assessment of NAFLD. The association between detected changes in hyperpolarized 13C MRI and progression of NAFLD will first be investigated in a preclinical model of the progression of NAFLD to NASH (Aim 1), specifically Zucker diabetic fatty (ZDF) rats fed a high fat diet. Two promising hyperpolarized probes of hepatic energy metabolism, [1- 13C]pyruvate and [2-13C]dihydroxyacetone, will be applied to these studies. These new hyperpolarized markers will be compared against gold standard measures of NAFLD derived from pathology, as well as biochemical assays of hepatic energy state and oxidative stress. Next, novel MRI methods will be developed to enable clinical translation of hyperpolarized 13C imaging of the liver (Aim 2). The proposed approach aims to enable dynamic free-breathing imaging of the entire liver by accelerated echo planar imaging (EPI) acquisition with sixteen-channel parallel imaging. To address the key challenge of array sensitivity calibration, a highly novel approach to parallel imaging will be deployed based on continuous tracking of receiver coil positions using an integrated manganese-55 MRI based fiducial marker system. Finally, initial clinical hyperpolarized [1- 13C]pyruvate MRI will be performed in normal subjects and patients with simple steatosis and NASH, with comparison to liver biopsy (Aim 3). By the end of this new five-year R01 Research Project Grant, we aim to deliver a valuable new clinical tool for non-invasively assessing the progression of NAFLD based on associated metabolic changes measured using hyperpolarized 13C MRI.

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）是一种以异位肝脂为特征的高度流行的疾病 与肥胖和2型糖尿病相关的累积。肝能量进行性紊乱 代谢是单纯性脂肪肝进展为非酒精性脂肪性肝炎（NASH）的基础， 具有进展为严重肝病状态的高风险。不幸的是，目前用于 监测NAFLD的方法是肝活检，它有很大的局限性，特别是它的高度侵入性。 超极化13 C磁共振成像（MRI）是一种新兴的分子成像方式， 以非侵入性方式进入中间能量代谢的独特能力， 在国际上的几个癌症研究中心进行人类研究， 心血管疾病这个新的R 01项目的目标是研究这种新技术的新应用。 分子影像学模式评估NAFLD。 超极化13 C MRI检测到的变化与NAFLD进展之间的关联将首先被研究。 在NAFLD进展为NASH的临床前模型中研究（目的1），特别是Zucker糖尿病 肥胖（ZDF）大鼠喂食高脂肪饮食。两个有前途的肝脏能量代谢超极化探针，[1- 13 C]丙酮酸和[2- 13 C]二羟基丙酮将用于这些研究。这些新的超极化标记 将与来自病理学的NAFLD的金标准措施以及生化指标进行比较。 肝脏能量状态和氧化应激的测定。下一步，将开发新的MRI方法， 肝脏超极化13 C成像的临床翻译（目的2）。建议的方法旨在使 通过加速回波平面成像（EPI）采集对整个肝脏进行动态自由呼吸成像， 16通道并行成像。为了解决阵列灵敏度校准的关键挑战， 并行成像的方法将基于使用 基于锰-55 MRI的集成基准标记系统。最后，初始临床超极化[1- 将在正常受试者和患有单纯性脂肪变性和NASH的患者中进行13 C]丙酮酸MRI， 与肝活检比较（目标3）。 到这项新的五年R 01研究项目资助结束时，我们的目标是提供一种有价值的新临床工具， 基于使用以下测量的相关代谢变化非侵入性地评估NAFLD的进展： 超极化13 C MRI。