MULTI-TISSUE MULTI-TRACER METABOLIC PHENOTYPING OF DIABETES WITH PRE-CLINICAL PET

使用临床前 PET 进行糖尿病的多组织多示踪剂代谢表型分析

基本信息

批准号：
8459006
负责人：
Kooresh Isaac Shoghi
金额：
$ 30.46万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-10 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459006
关键词：
Accounting Acetates Acids Address Adipose tissue Affect Algorithms Animal Model Blood Blood Circulation Blood Glucose CD36 gene Cardiovascular Diseases Carrier Proteins Cause of Death Complex Coupled Data Diabetes Mellitus Disease Epidemiology Etiology Failure Fatty Acids GLUT4 gene Gene Expression Profiling Genes Genomics Gluconeogenesis Glucose Glycerol Glycogen Hand Health Hepatic Hepatic artery Image Insulin Insulin Resistance Intervention Intracellular Accumulation of Lipids Intramuscular Kinetics Light Link Lipids Lipolysis Liver Measures Mediating Metabolic Metabolism Mind Modeling Muscle Myocardial Nature Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Outcome Measure Palmitates Pathogenesis Peripheral Phenotype Portal vein structure Positron-Emission Tomography Radioisotopes Research Research Design Rodent Stream System Systems Biology Time Tissues Tracer Translating Triglycerides Work blood glucose regulation clinical application diabetic diabetic patient experience fatty acid metabolism fatty acid oxidation glucose metabolism glucose uptake glycogenesis glycogenolysis in vivo insight insulin signaling interest knockout animal lipid biosynthesis mathematical model novel oxidation pre-clinical public health relevance research study response stable isotope uptake very low density lipoprotein triglyceride

项目摘要

DESCRIPTION (provided by applicant): Type 2 Diabetes (T2D) is a result of systemic disturbances in metabolism characterized mainly by impaired insulin action in peripheral tissues such as liver, muscle, and adipose tissue. In light of the highly interconnected and coordinated nature of substrate metabolism in health, and its failure in T2D, current research necessitates an integrated in-vivo "systems biology" strategy to investigate in-vivo multi-tissue metabolic alterations in the etiology of insulin resistance in obesity and diabetes. Pre-clinical PET is unique in that multiple tissues are in the field-of-view (FOV). This realization affords the opportunity to perform non-invasive multi-tissue quantitative imaging and metabolic phenotyping through multi-tracer experiments coupled with mathematical models of tracer kinetics. With that in mind and given our experience in quantifying myocardial substrate metabolism in rodents, we hypothesize that employing a similar approach will provide quantitative measures of substrate metabolism in liver, muscle, and adipose tissue. The metabolic tracers considered in this proposal include [11C]Palmitate for FA oxidation and triglycerides synthesis (storage), 18FTHA for fatty acid oxidation; [11C]Glucose for glucose oxidation and glycogen synthesis, 18FDG for glucose utilization, and [11C]Lactate as a potential imaging marker for gluconeogenesis. Given the dual-input function to the liver, in Specific Aim 1 we will validate and optimize an algorithm to reconstruct the liver dual-input function in multi- tracer imaging of hepatic substrate metabolism. With the liver dual input function at hand, in Specific Aim 2 we construct and validate compartmental models of 18FDG, [11C]Glucose, [11C]Lactate, [11C]Palmitate, [11C]Acetate, and 18FTHA metabolism through interventions that enhance the dynamic range of metabolic response. Having constructed and validated compartmental models for the tracers in this proposal, we assess and characterize metabolic disturbances in the pathogenesis of T2D by performing multi-tissue multi-tracer time-course metabolic phenotyping. In-vivo metabolic phenotyping will be coupled with expression array analysis to correlate genomics alterations to metabolic disturbances. We anticipate that successful completion of the proposed work will provide an integrated in-vivo metabolic phenotyping platform linking genomic alterations in transgenetic/knockout animal models of disease to multi-tissue metabolic disturbances in the study of T2D. In addition, the proposed work will facilitate characterization of the interplay between T2D and cardiovascular disease, among others highlighted in the proposal. Equally important, we anticipate that strategy and insights derived from this work will be translated to clinical applications.

描述（由申请人提供）：2型糖尿病（T2D）是全身代谢紊乱的结果，其特征主要是外周组织（例如肝脏、肌肉和脂肪组织）中的胰岛素作用受损。鉴于健康中底物代谢的高度相互关联和协调的性质，以及它在 T2D 中的失败，当前的研究需要一种综合的体内“系统生物学”策略来研究胰岛素抵抗病因中的体内多组织代谢改变在肥胖和糖尿病中。临床前 PET 的独特之处在于多个组织都位于视野 (FOV) 内。这一认识提供了通过多示踪剂实验与示踪动力学数学模型相结合进行非侵入性多组织定量成像和代谢表型分析的机会。考虑到这一点，并考虑到我们在量化啮齿动物心肌底物代谢方面的经验，我们假设采用类似的方法将提供肝脏、肌肉和脂肪组织中底物代谢的定量测量。本提案中考虑的代谢示踪剂包括用于FA氧化和甘油三酯合成（储存）的[11C]棕榈酸酯、用于脂肪酸氧化的18FTHA； [11C]葡萄糖用于葡萄糖氧化和糖原合成，18FDG用于葡萄糖利用，[11C]乳酸作为糖异生的潜在成像标记物。考虑到肝脏的双输入功能，在具体目标 1 中，我们将验证和优化一种算法，以在肝底物代谢的多示踪剂成像中重建肝脏双输入功能。借助现有的肝脏双输入功能，在特定目标 2 中，我们通过增强代谢反应的动态范围。在构建并验证了本提案中示踪剂的区室模型后，我们通过进行多组织多示踪剂时程代谢表型分析来评估和表征 T2D 发病机制中的代谢紊乱。体内代谢表型分析将与表达阵列分析相结合，将基因组改变与代谢紊乱相关联。我们预计，拟议工作的成功完成将提供一个集成的体内代谢表型平台，将转基因/基因敲除疾病动物模型中的基因组改变与 T2D 研究中的多组织代谢紊乱联系起来。此外，拟议的工作将有助于描述 T2D 与心血管疾病之间的相互作用，以及提案中强调的其他疾病。同样重要的是，我们预计从这项工作中得出的策略和见解将转化为临床应用。