Monitoring Hepatitis and Cirrhosis by 23Na MRS/MRI

本研究的总体目标是开发和验证非侵入性钠磁共振（MR） 检测和监测肝病发展为肝炎和肝硬化的技术。肝病是 美国第八大死因不管是什么原因， 许多肝脏疾病是：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提供了定量成像脂肪和水的优秀方法， 肝脏，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MR 来自细胞内和细胞外钠（Nai+和Nae+）的信号是异硫氰酸酯，或者是移位试剂（SR），或者是异硫氰酸酯。 多量子滤波器（MQF）技术是必要的，以区分两者。 当Na+的相关时间慢于其Larmar周期时观察到。由于高分子 在细胞内的浓度下，大多数MQF信号来自Naj+，只有很小的贡献来自Nae+。 该提议的三个主要假设是：1）单独的脂肪变性不会引起细胞内的任何变化。 跨膜Na+梯度、细胞能量学或pH; 2）肝炎导致总MQF 23 Na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，尽管细胞外空间的增加可能导致单量子（SQ）Nae+的增加， 信号;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+结合位点的数量由细胞外基质成分的增加引起。如果 如果这些假设是正确的，那么MQF 23 Na MR波谱和成像可以提供监测 肝炎和肝硬化的非侵入性进展。 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-。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。MR实验的结果将与 组织学和肝功能血液检查。此外，将实施和优化SQ和MQF 23 Na MRI 在3 T临床扫描仪上，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磁共振技术的提出，将有助于肝脏疾病的实验研究和诊断。 他们也可能被证明是有用的监测反应的治疗，这将有助于极大地设计更多的 治疗肝炎和肝硬化的有效策略。建议的研究亦会加强我们的 了解肝脏疾病不同阶段的能量状态和离子生理学之间的相互关系。

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.