Monitoring Hepatitis and Cirrhosis by 23Na MRS/MRI

描述（由申请人提供）：本研究的总体目标是开发和验证无创Na磁共振（MR）技术，以检测和监测肝病向肝炎和肝硬化的进展。肝脏疾病是美国第8大死亡原因。无论原因如何，许多肝脏疾病的3个主要病理阶段是：1）脂肪变性（脂肪积聚），2）肝炎（炎症和坏死）和3）肝硬化（纤维化和不可逆损伤）。1H MRI提供了对肝脏中的脂肪和水进行定量成像的极好方法，但脂肪变性是一种“良性”疾病，与肝脏疾病的严重程度无关，也不能预测其进展。目前，没有可靠的非侵入性方法来监测肝脏疾病的进展。跨膜Na+梯度对于细胞存活是必不可少的，并且被细胞损伤破坏。因为来自细胞内和细胞外钠（Nai+和Nae+）的MR信号是等离子体，所以需要移位试剂（SR）或多量子滤波器（MQF）技术来区分这2种。当Na+的相关时间慢于其Larmar周期时，观察到MQF Na MR信号。由于细胞内高分子浓度，大部分MQF信号来自Naj+，只有一小部分来自Nae+。该建议的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MQF 23 Na信号增加，这是由于[Nai+]增加和细胞内环境的变化，而MQF Nae+信号没有变化，尽管细胞外空间的增加可导致单量子（SQ）Nae+信号的增加;和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+的数量增加，细胞外基质成分增加导致的结合位点。如果这些假设是真的，那么MQF 23 Na MR波谱和成像可以提供无创监测肝炎和肝硬化进展的技术。将在脂肪肝、肝炎、肝硬化、纤维化和胆汁淤积的啮齿动物模型中使用体内Na SR，TmDOTP 5”来测试假设。1H和31 P MR技术也将用于检查脂肪积累，生物能量学，Na+和pH梯度之间的相关性。MR实验的结果将与组织学和肝功能的血液检查相关联。此外，SQ和MQF 23 Na MRI将在3 T临床扫描仪上实施和优化，并将证明人类肝脏定量23 Na MRI的可行性。MQF 23 Na MR的压倒性优势是它可以很容易地转化为人体研究。因此，23 Na磁共振技术将是非常有帮助的实验研究和肝脏疾病的诊断。它们也可能被证明对监测治疗反应有用，这将极大地有助于设计更有效的肝炎和肝硬化治疗策略。拟议的研究还将增强我们对肝脏疾病各个阶段能量状态和离子生理学之间相互关系的理解。

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.