Imaging Hepatic Gluconeogenesis with Hyperpolarized Dihydroxyacetone

项目概要 基于碳 13 的动态核极化 (DNP) 实验显示出巨大的潜力 测量活组织和体内的糖酵解通量和丙酮酸氧化。不过目前稳定的 显像剂无法测量肝脏糖异生 (GNG)。我们建议开发[2- 13C]二羟基丙酮 (DHA) 作为同时测量 GNG 和肝糖酵解的试剂。一个 来自 DHA 的三碳代谢物与己糖代谢物的比率将提供净肝脏 GNG 的指标。惠普 实验将与基于金标准[U-13C]丙酸盐/D2O 的 GNG 估计值和目标进行比较 糖酵解中间体的代谢组学特征。 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 2 将针对新陈代谢 在 C57BLKS/J 小鼠（对照）和广泛接受的 db/db 糖尿病模型的灌注肝脏中 肝脏葡萄糖产生过剩。我们还将使用方案评估该方法对治疗的敏感性 基于二甲双胍给药。 拨款的目标 3 转向将在 MD 安德森中心开发的 7 T 体内实验 该中心与 James Bankson 博士合作。班克森博士建议开发新的约束 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 适用于所有基于碳 13 的超极化成像方法。我们将使用 Zucker (fa/fa) 大鼠作为 Type 模型 二、糖尿病。后续实验将转回UF使用11 T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 糖尿病是一种世界范围内的流行病，预计到 2025 年将影响全球 3 亿人。 研究肝脏 GNG 的方法均基于示踪方法，需要接受一般性的研究 研究中心和大量同位素标记底物的管理。提出的方法 这里可以发展成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用于指导糖尿病和糖尿病的治疗计划 确定药物干预的有效性。此外，作为研究目标，新方法 允许同时测量糖酵解和 GNG。这一观察是一个全新的见解 肝脏代谢，并揭示净肝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.