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性敏感的代谢成像方法 脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH），以及与两者联系的过渡 病理生理状态。我们将使用超极化开发基于磁共振的代谢成像 13C和热偏振2H标记的底物。我们的测试床是C57BL/6N鼠标，饮食诱导和 疾病状态的遗传模型。该方法分析碳水化合物和脂肪酸代谢， 这些疾病已知会改变。 AIM 1。使用超极化[1-13C]和[2-13C]丙酮酸和 [2-13C]二羟基乙酮，我们将对肝丙酮酸氧化和 旋旋并且丙酮酸循环。 AIM 2。使用均匀的一个性一个性脂肪酸，我们将确定速率 同一模型中β-氧化和氧化还原生物学的变化。这些方法的结合将 在这些良好接受的模型中，对能量代谢的最全面分析 人类疾病。 AIM 3。我们将使用使用碳水和脂肪酸代谢成像测定法证实 淘汰测试我们范式基础的假设的小鼠。丙酮酸羧化酶敲除 小鼠下调丙酮酸蒸星。富马酸酯水力酶基因敲除小鼠是 下调的代谢将测试我们对克雷布斯周期周转的变化的敏感性。乙酰辅酶A。 羧化酶基因敲除小鼠将上调脂肪酸氧化。所有三个途径均已假设 作为NAFLD和NASH的发病机理和进展的基本要素。 关联 NAFLD和NASH现在是全球流行病，估计NAFLD的流行率高至 24％的世界人口。纳什有望超过肝炎，这是肝脏的第一起 在未来5年内在美国移植。在接下来的10年中，这种疾病预计是一种 1万亿美元的伯恩（Burnen）进入医疗保健系统。而纤维化的成像在某种程度上是纳什的诊断 进展，没有对炎症内在对炎症敏感的代谢成像技术 Nafld向Nash过渡。当前用于识别纳什的逐步范式缺乏正确的敏感性 对早期发展进行分类。当诊断出NASH时，疾病的临床管理会发生变化 贬低，变得更加昂贵。开发用于诊断和的代谢成像方法 NASH的分期将大大提高医疗保健实践，并有改善患者护理和 降低成本。