Imaging Hepatic Energy Metabolism in NAFLD/NASH

NAFLD/NASH 中肝脏能量代谢的成像

• 批准号: 10590690
• 负责人: MATTHEW E MERRITT
• 金额: $ 51.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590690
• 关键词: Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Anatomy; Biological Assay; Biology; Biopsy; Bypass; C57BL/6N Mouse; Caprylates; Carbohydrates; Carbon; Carnitine; Cessation of life; Citric Acid Cycle; Classification; Clinical; Clinical Management; Dangerousness; Deposition; Detection; Development; Diagnosis; Diagnostic; Diet; Dihydroxyacetone; Disease; Disease Management; Disease model; Elements; Energy Metabolism; Epidemic; FADH2; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Fumarate Hydratase; Futile Cycling; Genetic; Genetic Models; Goals; Healthcare; Healthcare Systems; Hemorrhage; Hepatic; Hepatitis; Heterogeneity; Image; Imaging Techniques; Imaging technology; Inflammation; Ionizing radiation; Kinetics; Knock-out; Knockout Mice; Label; Link; Lipids; Liver; Magnetic Resonance; Magnetic Resonance Elastography; Mass Spectrum Analysis; Measurement; Medium chain fatty acid; Metabolic; Metabolic Marker; Metabolic dysfunction; Metabolism; Methods; Modeling; Molecular; Monitor; Mus; NADH; Needle biopsy procedure; Oxidation-Reduction; Oxidative Phosphorylation; Palmitates; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Perfusion; Phosphoenolpyruvate Carboxylase; Population; Prevalence; Production; Pyruvate; Pyruvate Carboxylase; Pyruvate Kinase; Pyruvate Metabolism Pathway; Reactive Oxygen Species; Risk; Rodent Model; Sampling Biases; Signal Transduction; Staging; Surrogate Markers; Testing; Time; Tissues; Tracer; Transferase; Tricarboxylic Acids; United States; Water; Work; clinical imaging; clinical translation; cost; enzyme activity; fatty acid metabolism; fatty acid oxidation; global health; glucose metabolism; glucose production; human imaging; human model; imaging approach; imaging detection; imaging modality; imaging platform; improved; insight; kinetic model; liver metabolism; liver transplantation; loss of function; malic enzyme; metabolic imaging; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; oxidation; pyruvate dehydrogenase; translational potential; ultrasound

Project Summary There is an urgent need for development of metabolic imaging methods that are sensitive to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and to the transition linking the two pathophysiological states. We will develop magnetic resonance based metabolic imaging using hyperpolarized 13C and thermally polarized 2H-labeled substrates. Our testbed is the C57Bl/6N mouse, and diet induced and genetic models of the disease states. The approach assays both carbohydrate and fatty acid metabolism, which are known to be altered in these diseases. Aim 1. Using hyperpolarized [1-13C] and [2-13C]pyruvate and [2-13C]dihydroxyacetone, we will produce a multi-parametric assessment of hepatic pyruvate oxidation and anaplerosis, as well as pyruvate cycling. Aim 2. Using uniformly deuterated fatty acids, we will determine rates of β-oxidation and changes in redox biology in the same models. The combination of these approaches will yield the most comprehensive analysis of energy metabolism to date in these well-accepted models of the human disease. Aim 3. We will confirm both carbohydrate and fatty acid metabolism imaging assays using knock out mice that test the assumptions underlying our paradigms. The pyruvate carboxylase knockout mouse downregulates pyruvate anaplerosis. The fumarate hydratase knockout mouse is a model of downregulated metabolism that will test our sensitivity to changes in Krebs cycle turnover. The acetyl-CoA carboxylase knockout mouse will upregulate fatty acid oxidation. All three pathways have been hypothesized as essential elements of the pathogenesis and progression of NAFLD and NASH. Relevance NAFLD and NASH are now a worldwide epidemic, with some estimates of NAFLD prevalence as high as 24% of the world population. NASH is expected to surpass hepatitis as the number one cause of liver transplant in the United States within the next 5 years. Over the next 10 years, this disease is projected to be a 1 trillion dollar burden to the healthcare system. While imaging of fibrosis is somewhat diagnostic of NASH progression, there is no metabolic imaging technique that is sensitive to the inflammation endemic to the transition of NAFLD to NASH. Current stepwise paradigms for identifying NASH lack the sensitivity to correctly classify early development. When NASH is diagnosed, clinical management of the disease changes dramatically, becoming much more expensive. Development of a metabolic imaging method for diagnosis and staging of NASH would significantly enhance healthcare practice, with prospects for improving patient care and decreasing costs.

项目摘要 迫切需要开发对非酒精敏感的代谢成像方法。 脂肪肝(NAFLD)和非酒精性脂肪性肝炎(NASH)，以及两者之间的过渡 病理生理状态。我们将开发基于磁共振的代谢成像，使用超极化 13C和热极化的2H标记底物。我们的实验床是C57BL/6N小鼠，并诱导和 疾病状态的遗传模型。该方法同时检测碳水化合物和脂肪酸代谢， 已知在这些疾病中会发生改变。目的1.使用超极化的[1-13C]和[2-13C]丙酮酸和 [2-13C]二羟基丙酮，我们将产生一个多参数评估肝丙酮酸氧化和 复苏，以及丙酮酸循环。目标2.使用均一的重氢脂肪酸，我们将确定 在相同的模型中，β氧化和氧化还原生物学的变化。这些方法的组合将 在这些广为接受的模型中，产生迄今为止最全面的能量代谢分析 人类疾病。目的3.我们将使用以下方法确认碳水化合物和脂肪酸代谢成像分析 剔除那些测试我们范式背后的假设的老鼠。丙酮酸羧化酶基因敲除 小鼠下调丙酮酸脱氢反应。富马酸水合酶基因敲除小鼠是 新陈代谢下调，这将测试我们对Krebs周期周转变化的敏感性。乙酰辅酶A 羧化酶基因敲除的小鼠会上调脂肪酸氧化。所有这三条路径都是假设的 作为NAFLD和NASH发生和发展的重要因素。 相关性 NAFLD和NASH现在是一种世界性流行病，一些人估计NAFLD的流行率高达 占世界人口的24%。NASH有望超过肝炎成为导致肝脏疾病的头号原因 在未来5年内在美国进行移植。在接下来的10年里，这种疾病预计将成为一种 1万亿美元的医疗体系负担。虽然纤维化的成像在某种程度上是NASH的诊断 进展中，没有代谢成像技术对地方性炎症敏感 NAFLD向NASH的过渡。目前用于识别NASH的逐步范例缺乏对正确识别的敏感性 对早期发展进行分类。当NASH被诊断出来时，这种疾病的临床治疗就会改变 戏剧性地，变得更加昂贵。新陈代谢显像法的建立及临床应用 NASH的分期将显著加强医疗实践，具有改善患者护理和 降低成本。