Monitoring Hepatitis and Cirrhosis by 23Na MRS/MRI

通过 23Na MRS/MRI 监测肝炎和肝硬化

• 批准号: 7254856
• 负责人: NAVIN BANSAL
• 金额: $ 33.1万
• 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/7254856
• 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

DESCRIPTION (provided by applicant): 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 8th leading cause of death in the United States. Regardless of cause, the 3 major pathologic stages in many liver diseases are: 1) steatosis (fat accumulation), 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 necessary to discriminate between the 2. 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 a small contribution from Nae+. The 3 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 MQF 23Na 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 MQF 23Na 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 MQF 23Na 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.

描述（由申请人提供）：这项研究的总体目标是开发和验证非侵入性NA磁共振（MR）技术，以检测和监测肝病的肝炎和肝硬化的进展。肝病是美国第八大死亡原因。无论原因如何，许多肝病的三个主要病理阶段是：1）脂肪变性（脂肪积累），2）肝炎（炎症和坏死），以及3）肝硬化（纤维化和不可逆损害）。 1H MRI为肝脏中定量图像脂肪和水提供了出色的方法，但脂肪变性是一种“良性”状况，与肝病的严重程度无关或预测其进展。当前，没有可靠的无创方法来监测肝病的进展。跨膜Na+梯度对于细胞存活至关重要，并被细胞损伤所破坏。由于来自细胞内和细胞外钠（NAI+和NAE+）的MR信号是等方差的，因此要区分2个MQF Na MR信号在Na+的相关时间比其Larmar的相关时间较慢时观察到MQF Na MR信号是必要的。由于细胞内部的大分子浓度高，大多数MQF信号来自Naj+，只有NAE+的贡献很小。该提议的3个主要假设是：1）仅脂肪变性不会引起跨膜Na+梯度，细胞能量或pH的任何变化； 2）由于[NAI+]和细胞内环境的变化，肝炎总MQF 23NA信号增加，MQF NAE+信号没有变化，尽管细胞外空间的增加可能会导致单个Quantum（sq）NAE+信号的单个Quantum（SQ）NAE+信号的增加。 3）肝硬化/纤维化的发展导致MQF NAE+信号的增加，这是由于细胞外Na+结合位点的数量增加，导致细胞外基质成分的增加。如果这些假设是正确的，则MQF 23NA MR光谱法和成像可以提供无创肝炎和肝硬化进展的技术。这些假设将在脂肪肝，肝炎，肝硬化，纤维化和胆汁淤积的模型中进行检验肝脏功能也证明对监测对治疗的反应有用，这将有助于设计更有效的肝炎和肝硬化策略。