Imaging Hepatic Gluconeogenesis with Hyperpolarized Dihydroxyacetone

使用超极化二羟基丙酮对肝脏糖异生进行成像

• 批准号: 9175339
• 负责人: MATTHEW E MERRITT
• 金额: $ 35.4万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175339
• 关键词: Affect; Algorithms; Back; Bicarbonates; Blood Glucose; Bolus Infusion; Brain; C-Peptide; C57BLKS/J Mouse; Carbon; Child; Chronic; Citric Acid Cycle; Collaborations; Consumption; Depressed mood; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Dihydroxyacetone; Dose; Effectiveness; Embden Meyerhof pathway; Epidemic; Exhibits; Fasting; Fatty Acids; Genetic Models; Gluconeogenesis; Glucose; Glycerol; Glycolysis; Goals; Gold; Grant; Hepatic; Hexoses; Human; Image; Institutes; Insulin; Insulin Resistance; Intervention; Intracellular Space; Ionizing radiation; Label; Life; Light; Liver; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Metformin; Methodology; Methods; Modeling; Monitor; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear; Pathology; Pathway interactions; Pharmacologic Substance; Phosphoenolpyruvate Carboxylase; Physiologic pulse; Physiological; Propionates; Protocols documentation; Pyruvate; Rattus; Regulation; Research; Rodent Model; Safety; Sum; System; Targeted Research; Techniques; Testing; Time; Tissues; Tracer; Trioses; Vulnerable Populations; base; clinically relevant; db/db mouse; diabetic; diabetic rat; effectiveness measure; feeding; glucose output; glucose production; hepatic gluconeogenesis; imaging agent; imaging modality; imaging system; in vivo; inorganic phosphate; insight; liver metabolism; magnetic field; metabolomics; molecular imaging; mouse model; new technology; oxidation; pre-clinical; pyruvate dehydrogenase; reconstruction; research study; small molecule; treatment planning; treatment response

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.

项目摘要 基于碳-13的动态核极化（DNP）实验已经显示出巨大的潜力， 测量活组织和体内的糖酵解通量和丙酮酸氧化。然而，目前稳定的 成像剂不能测量肝再生（GNG）。我们建议开发[2- 13 C]二羟基丙酮（DHA）作为同时测量GNG和肝糖酵解的试剂。一 来自DHA的三碳与己糖代谢物的比率将提供净肝GNG的量度。HP 实验将与金标准[U-13 C]丙酸盐/D2 O的GNG估计值进行比较， 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将针对代谢 在C57 BLKS/J小鼠（对照）和公认的db/db糖尿病模型的灌注肝脏中， 肝葡萄糖过度生成。我们还将评估该方法的敏感性治疗使用的协议 基于二甲双胍给药。 补助金的目标3过渡到将在MD安德森开发的7 T体内实验 中心与詹姆斯·班克森博士合作。Bankson博士建议开发新的约束 重建算法，将提高定位的13 C图像，一个极具挑战性的问题 所有基于超极化碳13的成像方法。我们将使用Zucker（fa/fa）大鼠作为类型 II型糖尿病。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 糖尿病是一种世界性流行病，预计到2025年将影响全球3亿人。 用于研究肝GNG的方法都是基于示踪剂方法学，其需要进入一般的 研究中心和大量同位素标记底物的管理。提出的方法 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的治疗计划， 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。这一观察是一个全新的见解， 肝代谢，并提请光净肝GNG的性质;它是糖酵解和 组织内的致炎活性。