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

描述(申请人提供)：2型糖尿病(T2D)是一种全身性代谢紊乱的结果，主要表现为周围组织如肝脏、肌肉和脂肪组织的胰岛素作用受损。鉴于底物代谢在健康中的高度相互联系和协调的本质，以及它在T2D中的失败，目前的研究需要一种整合的体内“系统生物学”策略来研究肥胖和糖尿病胰岛素抵抗病因中体内多组织代谢变化。临床前PET的独特之处在于多个组织处于视野(FOV)内。这一认识提供了通过多示踪剂实验结合示踪剂动力学数学模型执行非侵入性多组织定量成像和代谢表型的机会。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，使用类似的方法将提供肝脏、肌肉和脂肪组织底物代谢的定量测量。本建议中考虑的代谢示踪剂包括用于脂肪酸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，用于葡萄糖氧化和糖原合成的[11C]葡萄糖，用于葡萄糖利用的18FDG，以及作为潜在的糖异生的成像标志物的[11C]乳酸。在给定肝脏双输入函数的情况下，在特定目标1中，我们将验证和优化一种在肝脏底物代谢的多示踪成像中重建肝脏双输入函数的算法。有了肝脏的双重输入功能，在特定的目标2中，我们通过提高代谢反应的动态范围的干预，构建并验证了18FDG、[11C]葡萄糖、[11C]乳酸、[11C]棕榈酸酯、[11C]醋酸酯和18FTHA代谢的分室模型。在构建和验证了本方案中示踪剂的分室模型后，我们通过进行多组织多示踪剂时程代谢表型分析，评估和表征了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，以将基因组学变化与代谢紊乱联系起来。我们预计，拟议工作的成功完成将提供一个整合的体内代谢表型分析平台，将转基因/基因敲除疾病动物模型中的基因组变化与T2D研究中的多组织代谢障碍联系起来。此外，拟议的工作将有助于描述T2D和心血管疾病之间的相互作用，以及提案中强调的其他内容。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。

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.