Monitoring Hepatitis and Cirrhosis by 23Na MRS/MRI

通过 23Na MRS/MRI 监测肝炎和肝硬化

• 批准号: 7468554
• 负责人: NAVIN BANSAL
• 金额: $ 4.27万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468554
• 关键词: Acute; Acute Liver Failure; Alcohol consumption; Animal Model; Benign; Binding Sites; Bioenergetics; Biopsy; Blood Tests; Carbon Tetrachloride; Cause of Death; Cell Survival; Cells; Cholestasis; Chronic; Cirrhosis; Clinical; Clinical Management; Condition; Development; Diabetes Mellitus; Diagnosis; Diet; Dimethylnitrosamine; Endotoxins; Environment; Evaluation; Event; Extracellular Matrix; Extracellular Space; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Galactosamine; Goals; Hepatic; Hepatitis; Histology; Human; Hydrochloride Salt; Image; Imaging Techniques; Inflammation; Injury; Ions; Lead; Liver; Liver diseases; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Methionine; Methods; Modeling; Monitor; Necrosis; Numbers; Obesity; Pathologic; Pathway interactions; Patients; Physiology; Rattus; Reagent; Research; Research Personnel; Rodent Model; Severities; Signal Transduction; Sodium; Staging; Techniques; Testing; Thioacetamide; Time; Translating; United States; Water; aging population; body system; choline deficient diet; design; extracellular; feeding; healthy volunteer; human study; in vivo; liver function; macromolecule; non-alcoholic; pH gradient; programs; quantum; research study; response

The overall goal of this research is to develop and validate noninvasive Na magnetic resonance(MR) techniques to detect and monitor the progression of liver diseases to hepatitis and cirrhosis. Liver diseases are the eighth leading cause of death in the United States. Regardless of cause, the three major pathologic stages in many liver diseases are:1) steatosis (fataccumulation), 2) hepatitis (inflammation and necrosis), and 3) cirrhosis (fibrosis and irreversible damage). 1H MRI provides excellent methods to quantitatively image fat and water in the liver, but steatosis is a "benign" condition and does not correlate with the severity of liver disease or predict its progression. Currently, there are no reliable noninvasive methods for monitoring the progression of liver diseases. A transmembrane Na+ gradient is essential for cell survival and is disrupted by cellular damage. Because MR signal from both intra- and extracellular sodium (Nai+ and Nae+) is isochronous, either a shift reagent (SR) or the multiple-quantum-filter (MQF) technique is necessaryto discriminate between the two.An MQF Na MR signal is observed when the correlation time of Na+ is slower than its Larmar period. Because of the high macromolecule concentration inside the cells, a majority of MQF signal comes from Naj+, with only small contribution from Nae+. The three main hypotheses of this proposal are that: 1) steatosis alone does not cause any changes in the transmembrane Na+ gradient, cellular energetics, or pH; 2) hepatitis leads to an increase in total MQF23Na signal, due to both an increase in [Nai+] and a change in the intracellular environment, and no change in the MQF Nae+ signal, although an increase in extracellular space may lead to an increase in the single-quantum (SQ) Nae+ signal; and 3) development of cirrhosis/fibrosis leads to an increase in the MQF Nae+ signal due to an increase in the number of extracellular Na+ binding sites resulting from the increase in extracellular matrix components. If these hypotheses are true, then MQF 23Na MR spectroscopy and imaging can provide techniques to monitor progress of hepatitis and cirrhosis noninvasively. The hypotheses will be tested in rodent models of fatty liver, hepatitis, cirrhosis, fibrosis, and cholestasis using an in vivo Na SR, TmDOTP5". 1H and 31P MR techniques will also be used to examine the correlation between fat accumulation, bioenergetics, and Na+ and pH gradients. The results of MR experiments will be correlated with histology and blood tests for liver function. In addition, SQ and MQF23Na MRI will be implemented and optimized on a 3T clinical scanner, and the feasibility of quantitative 23Na MRI of the liver in humans will be demonstrated. The overwhelming advantage of MQF23Na MR is that it can be readily translated to human studies. Thus, the proposed 23Na MR techniques will be very helpful in both experimental studies and diagnosis of liver diseases. They may also prove useful for monitoring response to therapy, which will help tremendously in designing more effective strategies for treatment of hepatitis and cirrhosis. The proposed research will also enhance our understanding of the interrelationship between energy status and ion physiology in various stages of liver disease.

本研究的总体目标是开发和验证无创性钠磁共振(MR) 检测和监测肝病发展为肝炎和肝硬变的技术。肝病有 是美国第八大死因。不管原因如何，三个主要的病理阶段 许多肝脏疾病是：1)脂肪变性(脂肪堆积)，2)肝炎(炎症和坏死)，3)肝硬变 (纤维化和不可逆转的损害)。1HMRI提供了定量成像脂肪和水分的极佳方法 肝脏，但脂肪变性是一种“良性”的情况，与肝脏疾病的严重程度无关，也不能预测其 进步。目前，还没有可靠的无创方法来监测肝脏疾病的进展。 跨膜Na+梯度是细胞生存所必需的，并被细胞损伤所破坏。因为先生 来自细胞内和细胞外的钠(NaI+和NaE+)的信号是等时的，要么是位移试剂(SR)，要么是 多量子滤波(MQF)技术是区分这两者的必要手段。 当Na+的关联时间慢于其Larmar周期时观察到。因为它是高分子的 在细胞内，大部分MQF信号来自NaJ+，NaE+的贡献很小。 这一建议的三个主要假设是：1)脂肪变性本身不会引起任何改变 跨膜Na+梯度、细胞能量学或pH；2)肝炎导致总MQF23Na信号增加， 由于[NaI+]的增加和细胞内环境的变化，而MQF NAE+没有变化 信号，尽管胞外空间的增加可能导致单量子(SQ)NAE+的增加 3)肝硬变/纤维化的发展导致MQF NAE+信号的增加，这是由于 由于细胞外基质成分的增加而导致的细胞外Na+结合部位的数量。如果 这些假设是真的，那么MQF 23Na磁共振波谱和成像可以提供监测技术 肝炎和肝硬变的无创性研究进展。 这些假说将在脂肪肝、肝炎、肝硬变、纤维化和胆汁淤积的啮齿动物模型中进行测试，使用 体内的Na SR，TmDOTP5“。1H和31P磁共振技术也将被用来检查 脂肪积累，生物能量学，以及Na+和pH梯度。磁共振实验的结果将与 组织学和血液检测肝功能。此外，还将实施和优化SQ和MQF23Na磁共振 在一台3T临床扫描仪上，将论证人体肝脏定量23Na磁共振成像的可行性。 MQF23Na MR的压倒性优势是它可以很容易地转化为人体研究。因此， 提出的~(23)Na磁共振技术将对肝脏疾病的实验研究和诊断有很大的帮助。 它们还可能被证明对监测治疗反应很有用，这将极大地帮助设计更多的 肝炎和肝硬变的有效治疗策略。拟议的研究还将加强我们的 了解肝病不同阶段能量状态与离子生理的相互关系。