Nuclear Overhauser enhancement (NOE) MR imaging of choline phospholipids and their metabolism

项目摘要 根据定义，癌细胞是高度增殖的，并且生长迅速。一般来说，增殖率越高， 肿瘤的侵袭性就越强为了维持高增殖率，膜胆碱 磷脂代谢被上调以提供细胞生物量用于加速生长并维持细胞生长。 存活力，这引起膜胆碱磷脂及其代谢物的含量变化。 因此，这些分子的含量与肿瘤的侵袭性有很强的相关性。提高 为了预测癌症的预后和治疗监测，非常希望具有分子和代谢成像， 方法揭示胆碱磷脂及其代谢。虽然有几个入侵 虽然先前已经开发了研究胆碱磷脂的技术，但迄今为止还没有方法 可以高灵敏度地评估胆碱磷脂及其体内代谢。化学交换 饱和转移（CEST）MRI是一种新兴的分子成像方法，其灵敏度远高于 夫人最近，我们注意到体内NOE介导的饱和转移信号在水的-1.6ppm处， 称为NOE（-1.6），其在肿瘤中也降低。对主要组织成分的体模研究表明， 它来自胆碱磷脂。基于这些初步数据，我们假设（1）NOE（-1.6）是一个 通过磷脂胆碱头部基团和水之间的偶极相互作用的饱和转移效应;（2） 肿瘤中NOE（-1.6）信号的降低是由于胆碱磷脂的减少， 胆碱磷脂代谢在目标1中，我们将通过使用修饰的磷脂来验证假设1 样本，这将表明NOE（-1.6）测量胆碱磷脂代谢的能力，其中 胆碱头基被磷脂酶裂解，NOE（-1.6）信号消失。在目标2中， 我们将通过将NOE（-1.6）与整个组织的胆碱磷脂含量图相关联来验证假设2。 通过基质辅助激光解吸/电离成像质谱（MALDI IMS）获得的切片， 动物肿瘤模型，这将表明NOE（-1.6）测量改变的胆碱磷脂的能力 以及它们在肿瘤中的代谢;我们还将开发一种新的CEST定量方法，称为绝热法。 双曲正割（HS）-CEST，它用HS反转脉冲代替传统饱和 脉冲，并且改变每单位时间的HS脉冲的数量以在两次扫描中引起不同的CEST效应，但是改变 使HS脉冲幅度保持恒定的平均饱和功率，使背景直接饱和 MT是一样的。两次扫描的相减将从背景信号中隔离CEST效应，这解决了 传统CEST成像中的非特异性、B1和B 0不均匀性的挑战性问题。通过 这三个目标，我们将提供一个独特的MRI方法来测量胆碱磷脂及其代谢 具有高灵敏度，这将允许单独的假设驱动的肿瘤临床前和临床研究。

PROJECT SUMMARY Cancer cells by definition are highly proliferative and grow rapidly. In general, the higher the proliferation rate, the more aggressive the tumor tends to be. To maintain the high proliferation rate, membrane choline phospholipid metabolism is upregulated to provide cellular biomass for accelerated growth and maintain viability, which causes changes in the content of both membrane choline phospholipids and their metabolites. Therefore, the content of these molecules have strong association with tumor aggressiveness. To improve the prognosis and treatment-monitoring of cancer, it is highly desirable to have a molecular and metabolic imaging approach to reveal the choline phospholipids and their metabolism. However, although several invasive techniques have been previously developed to study choline phospholipids, there are no methods to date that can assess choline phospholipids and their metabolism in vivo with high sensitivity. Chemical exchange saturation transfer (CEST) MRI is an emerging molecular imaging method with much higher sensitivity than MRS. Recently, we have noticed an in vivo NOE-mediated saturation transfer signal at -1.6 ppm from water, termed NOE(-1.6), which also decrease in tumors. Phantom studies on major tissue components suggest that it is from choline phospholipids. Based on these preliminary data, we hypothesize that (1) the NOE(-1.6) is a saturation transfer effect via dipolar interactions between phospholipid choline head group and water; (2) the reduced NOE(-1.6) signal in tumor is due to the reduced choline phospholipids caused by the upregulated choline phospholipid metabolism. In Aim1, we will validate hypothesis #1 by using modified phospholipid samples, which will suggest the capability of NOE(-1.6) to measure choline phospholipid metabolism in which the choline head group is cleaved by phospholipase enzymes and the NOE(-1.6) signal disappears. In Aim2, we will validate hypothesis #2 by correlating NOE(-1.6) with maps of choline phospholipid contents of whole slices obtained by matrix-assisted laser desorption /ionization imaging mass spectrometry (MALDI IMS) on animal tumor models, which will suggest the capability of NOE(-1.6) to measure altered choline phospholipids and their metabolism in tumors; We will also develop a novel CEST quantification method, termed adiabatic Hyperbolic Secant (HS)-CEST, which substitutes HS inversion pulses in place of conventional saturation pulses, and vary the numbers of HS pulses per unit time to induce different CEST effect in two scans, but vary the HS pulse amplitude to maintain constant average saturation power so that the background direct saturation and MT are same. Subtraction of the two scans will isolate CEST effect from background signals, which solves the challenging issues of non-specificity, B1, and B0 inhomogeneity in conventional CEST imaging. Through these 3 aims, we will provide a unique MRI method for measuring choline phospholipids and their metabolism with high sensitivity, which will allow separate hypothesis-driven preclinical and clinical studies of tumors.