Fructose Metabolism as a Biomarker for Monitoring Hepatocellular Carcinoma

项目概要/摘要（描述） 与资金公告的使命一致，即利用工程原理解决生物医学领域的问题。 科学，这项研究提出开发新的工具，以监测肝细胞癌（HCC）的基础上，肝细胞癌的变化， 果糖代谢肝细胞癌是肝脏的恶性肿瘤，其预后并不仅仅取决于肿瘤的大小 而且对肝功能也有影响代谢综合征的流行也出现了非酒精性脂肪肝 （NAFLD）是美国HCC的主要原因。虽然这种HCC的发病率有所增加，但仍存在未满足的需求 用于能够早期检测和分期HCC的收费。这项研究建议开发新的生物标志物来追踪癌症 进展基于HCC中果糖代谢的丧失。 我们假设果糖代谢在肝癌的发展中丢失，可以用来追踪HCC。这是 基于已发表的文献和我们最近的实验表明蛋白质参与肝脏果糖代谢 包括己酮糖激酶（KHK）在HCC中下调。这些观察结果构成了我们假设的基础 果糖代谢是正常肝脏的保护区，在肝癌中被下调。因此，发展 基于血液的测试来测量血液中的果糖水平将告知肝功能。一种互补的代谢 基于超极化磁共振成像（HP-MRI）的成像生物标志物将提供实时、空间、 信息. HP-MRI是一种新的成像技术，可改善13 C标记分子的检测， 代谢通量的定量，目前正在进行临床试验。在目标1中，我们将测量血液和组织水平 在NAFLD背景下的HCC小鼠模型中静脉注射果糖后，我们将使用质量 光谱，在与药学院的新合作。然后我们将研究这一行动的机制， 通过聚焦于转录因子肝细胞核因子4 α（HNF 4A）来观察这种现象。在目标2中，我们将优化 [2- 13 C]果糖的极化，以能够检测正常和HCC小鼠中的KHK活性。 该项目提出了一种基于新的生物学观察的创新和定量方法来跟踪HCC 肝细胞癌患者肝脏代谢改变的证据来自生物化学、代谢组学和MR等不同背景的研究者 工程师们已经集合起来，以确保成功。该项目的完成将提供互补的，可翻译的 监测HCC的技术。

Project Summary/Abstract (Description) Consistent with the mission of the funding announcement to use engineering principles to solve problems in biomedical science, this research proposes to develop new tools to monitor hepatocellular carcinoma (HCC) based on changes in hepatic fructose metabolism. HCC is a malignancy of the liver and the prognosis of the disease does not solely depend on tumor stage but also on liver function. The prevalence of metabolic syndrome has also seen non-alcoholic fatty liver disease (NAFLD) as the leading cause of HCC in the US. While there is an increase incidence of this HCC, there is an unmet need for tolls that enable early detection and staging of HCC. This study proposes to develop new biomarkers to track cancer progression based on the loss of fructose metabolism in HCC. We hypothesize that fructose metabolism is lost in the development of liver cancer and can be used track HCC. This is based on published literature and our recent experiments showing proteins involved in hepatic fructose metabolism including ketohexokinase (KHK) are down regulated in HCC. These observations form the foundation of our hypothesis that fructose metabolism is the preserve of the normal liver and is down regulated in liver cancer. Therefore, development of a blood-based test to measure fructose levels in the blood will inform on hepatic function. A complementary metabolic imaging biomarker based on hyperpolarized magnetic resonance imaging (HP-MRI) will provide real-time, spatial information. HP-MRI is a new imaging technology that improves detection of 13C-labeled molecules, enabling non-invasive quantification of metabolic flux and is currently undergoing clinical trials. In Aim 1, we will measure blood and tissue levels of fructose after an intravenous fructose injection in a mouse model of HCC in a background of NAFLD. We will use mass spectrometry, in a new collaboration with the School of Pharmacy. We will then investigate the mechanism of action of this phenomenon by focusing on the transcription factor, hepatocyte nuclear factor 4 alpha (HNF4A). In Aim 2, we will optimize polarization of [2-13C] fructose, to enable detection of KHK activity in normal and HCC mice. This project proposes to develop innovative and quantitative methods to track HCC based on a novel biological observation of altered liver metabolism in HCC. Investigators from diverse backgrounds such as biochemistry, metabolomics and MR engineering have been assembled to ensure success. The completion of this project will deliver complementary, translatable technologies for monitoring HCC.