Imaging Hepatic Gluconeogenesis with Hyperpolarized Dihydroxyacetone

项目摘要 基于碳13的动态核极化(DNP)实验显示出巨大的潜力 测量活体组织和活体中的糖酵解通量和丙酮酸氧化。然而，目前稳定的 显像剂不能测量肝脏糖异生(GNG)。我们建议开发[2- 13C]二羟基丙酮(DHA)作为一种同时测定GNG和肝脏糖酵解的试剂。一个 来自DHA的三碳与己糖代谢物的比率将提供肝脏净GNG的度量。惠普 实验将与基于[U-13C]丙酸盐/D2O的黄金标准GNG估计值进行比较，并与目标GNG进行比较 糖酵解中间体的代谢组谱。 我们将在三种不同的啮齿动物模型中测量GNG和糖酵解。目标1和目标2将针对新陈代谢 在C57BLKS/J小鼠(对照)和公认的糖尿病db/db模型的灌流肝脏中， 肝脏葡萄糖产生过多。我们还将使用一种方案评估该方法对治疗的敏感性 基于二甲双胍的给药。 目标3赠款将在MD Anderson开发的7T下过渡到活体实验 该中心与詹姆斯·班克森博士合作。班克森博士建议开发新的受限于 重建算法将增强13C图像的定位，这是一个极具挑战性的问题 用于所有基于超极化碳-13的成像方法。我们将使用Zucker(fa/fa)大鼠作为Type 二、糖尿病。随后的实验将被转移回UF，以使用11T成像完成 该系统可通过麦克奈特脑研究所的国家高磁场实验室获得。 相关性 糖尿病是一种世界性流行病，预计到2025年全球将有3亿人受到影响。 研究肝脏GNG的方法都是基于示踪方法，这些方法需要进入一般的 研究中心和大量同位素标记底物的管理。提出的方法 可以将其开发为与标准磁共振成像集成的单一检查 协议。我们预计，所提出的方法可以用于指导糖尿病的治疗计划和 确定药物干预的有效性。此外，作为研究对象，新方法 允许同时测量糖酵解和GNG。这一观察结果是对 肝脏代谢，并揭示了肝脏净GNG的性质；它是糖酵解和 组织内的糖异生活动。

Project Summary Carbon-13 based dynamic nuclear polarization (DNP) experiments have shown tremendous potential for measuring glycolytic flux and pyruvate oxidation in living tissues and in vivo. However, the current stable of imaging agents cannot measure hepatic gluconeogenesis (GNG). We propose to develop [2- 13C]dihydroxyacetone (DHA) as an agent for measuring both GNG and hepatic glycolysis simultaneously. A ratio of three-carbon to hexose metabolites derived from DHA will provide a metric of net hepatic GNG. HP experiments will be compared to gold standard [U-13C]propionate/D2O based estimates of GNG and to targeted metabolomic profiles of glycolytic intermediates. We will measure GNG and glycolysis in three different rodent models. Aims 1 and 2 will target metabolism in the perfused liver of the C57BLKS/J mouse (control) and the well-accepted db/db model of diabetes and hepatic glucose overproduction. We will also assess the sensitivity of the method to treatment using a protocol based on metformin administration. Aim 3 of the grant transitions to in vivo experiments at 7 T that will be developed at the MD Anderson Center in collaboration with Dr. James Bankson. Dr. Bankson proposes to develop new constrained reconstruction algorithms that will enhance the localization of the 13C images, an extremely challenging issue for all hyperpolarized carbon-13 based imaging methods. We will use the Zucker (fa/fa) rat as a model of Type II diabetes. Subsequent experiments will be transferred back to UF for completion using the 11 T imaging system available through the National High Magnetic Field Lab at the McKnight Brain Institute. Relevance Diabetes is a worldwide epidemic that is projected to affect 300 million people worldwide by the year 2025. Methods for studying hepatic GNG are all based on tracer methodologies that require admittance to a general research center and administration of large amounts of isotopically labeled substrates. The method proposed here could be developed into a single exam that is integrated with standard magnetic resonance imaging protocols. We anticipate that the method proposed could be used to guide treatment plans for diabetes and determine the effectiveness of pharmacological interventions. Also, as a research target, the new method allows simultaneous measures of glycolysis and GNG. This observation is a fundamentally new insight into hepatic metabolism, and draws into light the nature of net hepatic GNG; it is the sum of the glycolytic and gluconeogenic activities within the tissue.