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。但是，当前的稳定 成像剂无法测量肝糖异生（GNG）。我们建议开发[2- 13C]二羟基丙酮（DHA）作为同时测量GNG和肝糖酵解的药物。一个 从DHA得出的三碳与己糖代谢产物的比率将提供净肝GNG的度量。惠普 将将实验与基于GNG的基于金标准[U-13C]丙酸/d2o估计值 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2将针对新陈代谢 在C57BLKS/J小鼠的灌注肝脏中（对照）和糖尿病的DB/DB模型和 肝葡萄糖过量生产。我们还将评估该方法使用方案治疗的敏感性 基于二甲双胍给药。 目标3的赠款过渡到将在MD Anderson开发的7 t的体内实验 与詹姆斯·班克森（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图像的本地化，这是一个极具挑战性的问题 对于所有基于超极化的基于碳13的成像方法。我们将使用Zucker（FA/FA）大鼠作为类型的模型 II糖尿病。随后的实验将使用11 t成像转移回UF进行完成 通过McKnight Brain Institute的国家高磁场实验室获得的系统。 关联 糖尿病是一种全球流行病，预计到2025年将影响全球3亿人。 研究肝GNG的方法都是基于需要通用的示踪方法 研究中心和管理大量同位素标记的底物。提出的方法 这里可以发展为与标准磁共振成像集成的单个考试 协议。我们预计提出的方法可用于指导糖尿病的治疗计划和 确定药理干预措施的有效性。另外，作为研究目标，新方法 允许同时测量糖酵解和GNG。这种观察是对 肝代谢，并阐明了网络肝gng的本质；这是糖酵解和 组织内的糖原活性。