Monitoring Hepatitis and Cirrhosis by 23Na MRS/MRI

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钠磁共振(MR)技术，以检测和监测肝脏疾病发展为肝炎和肝硬化的过程。肝病是美国第八大死因。无论病因如何，许多肝脏疾病的三个主要病理阶段是：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)。1H MRI提供了对肝脏中的脂肪和水进行定量成像的极佳方法，但脂肪变性是一种“良性”的情况，与肝脏疾病的严重程度或预测其进展无关。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。由于胞内和胞外Na+(NaI+和NaE+)的MR信号是同步的，因此需要移动剂(SR)或多量子滤光器(MQF)技术来区分两者。当Na+的关联时间慢于其Larmar周期时，可以观察到MQF Na MR信号。由于细胞内的大分子浓度较高，MQF信号大部分来自NaJ+，NaE+的贡献很小。这一提议的3个主要假设是：1)脂肪变性本身不会引起跨膜Na+梯度、细胞能量学或pH的任何变化；2)肝炎导致总的MQF 23Na信号增加，这是由于细胞内环境的改变和[NaI+]的增加，而MQF NAE+信号没有改变，尽管细胞外空间的增加可能导致单量子(SQ)NAE+信号的增加；以及3)由于细胞外基质成分的增加导致细胞外Na+结合部位的增加，肝硬变/纤维化导致MQF NAE+信号的增加。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非侵入性监测肝炎和肝硬变进展的技术。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使用体内的Na SR TmDOTP5进行测试。1H和31P磁共振技术也将被用来检验脂肪积累、生物能量学以及Na+和pH梯度之间的相关性。磁共振实验的结果将与组织学和肝功能的血液测试相关联。此外，SQ和MQF 23Na MRI将在3T临床扫描仪上进行实施和优化，并将论证人体肝脏23Na MRI定量的可行性。MQF 23Na MR的压倒性优势是它可以很容易地转化为人体研究。因此，所提出的~(23)Na磁共振技术将对肝脏疾病的实验研究和诊断非常有帮助。它们还可能被证明对监测治疗反应有用，这将极大地帮助设计更有效的治疗肝炎和肝硬变的策略。这项拟议的研究还将加深我们对肝病不同阶段能量状态和离子生理之间的相互关系的理解。

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.