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

项目摘要/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型糖尿病相关的蓄积。进行性肝能量紊乱 代谢是单纯性脂肪肝发展为非酒精性脂肪性肝炎(NASH)的基础，NASH是一种疾病 这会带来进展到严重肝病状态的高风险。不幸的是，当前的方法 监测非酒精性脂肪肝是肝脏活检，具有较大的局限性，尤其是侵袭性较高。 超极化13C磁共振成像(MRI)是一种新兴的分子成像方式，具有 以非侵入性方式获得中介能量代谢的独特能力，目前 在国际上几个地点进行癌症研究和人类研究的人类研究 心血管疾病。这个新的R01项目的目标是研究这种新的 分子影像技术在NAFLD评估中的应用。 超极化~(13)C磁共振成像检测到的变化与NAFLD进展之间的联系将首先是 NAFLD进展为NASH的临床前模型研究(目标1)，特别是Zucker糖尿病 肥胖(ZDF)大鼠喂食高脂肪食物。两种很有前途的肝脏能量代谢超极化探针[1- 13C]丙酮酸和[2-13C]二羟基丙酮将应用于这些研究。这些新的超极化标记 将与来自病理学和生化的非酒精性脂肪肝的黄金标准进行比较 肝脏能量状态和氧化应激的测定。接下来，将开发新的MRI方法，以实现 肝脏超极化13C成像的临床翻译(目标2)。拟议的方法旨在使 通过加速回波平面成像(EPI)采集全肝的动态自由呼吸成像 16通道并行成像。为了解决阵列灵敏度校准的关键挑战，一种非常新颖的 将部署基于连续跟踪接收器线圈位置的并行成像方法 集成的基于MANN-55MRI的基准标记系统。最后，最初的临床超极化[1- 13C]丙酮酸核磁共振成像将在正常人和单纯性脂肪变性和NASH患者中进行， 与肝活检的比较(目标3)。 到这个新的五年R01研究项目拨款结束时，我们的目标是提供一个有价值的新临床工具 非侵入性评估NAFLD进展的基础上相关的代谢变化测量使用 超极化~(13)C磁共振。

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.