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

项目总结 根据定义，癌细胞是高度增殖和快速生长的。一般来说，核扩散速度越高， 肿瘤的侵袭性就越强。为维持高增殖率，膜胆碱 磷脂代谢被上调以提供细胞生物量以加速生长和维持 活性，引起细胞膜胆碱磷脂及其代谢物含量的变化。 因此，这些分子的含量与肿瘤的侵袭性有很强的相关性。为了改善 癌症的预后和治疗监测，分子和代谢成像是非常可取的 揭示胆碱磷脂及其代谢的途径。然而，尽管有几个入侵 以前已经开发了研究胆碱磷脂的技术，到目前为止还没有方法 可高灵敏度地评价胆碱磷脂及其体内代谢。化学交换 饱和转移(CEST)磁共振成像是一种新兴的分子成像方法，其灵敏度远高于 最近，我们注意到来自水的体内NOE介导的饱和转移信号为-1.6ppm， 称为NOE(-1.6)，在肿瘤中也是减少的。对主要组织成分的幻影研究表明 它来自胆碱磷脂。根据这些初步数据，我们假设(1)NOE(-1.6)是一个 磷脂胆碱头基团与水之间偶极相互作用的饱和转移效应； 肿瘤中NOE(-1.6)信号的减少是由于上调导致胆碱磷脂减少所致 胆碱磷脂代谢。在Aim1中，我们将使用修饰的磷脂来验证假设#1 样品，这将表明NOE(-1.6)有能力测量胆碱磷脂代谢，其中 胆碱头基团被磷脂酶切割，NOE(-1.6)信号消失。在Aim2， 我们将通过将NOE(-1.6)与整体胆碱磷脂含量图相关联来验证假设2 基质辅助激光解吸电离成象质谱仪(MALDI IMS)获得的薄片 动物肿瘤模型，表明NOE(-1.6)有能力测量改变的胆碱磷脂 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 双曲正割(HS)-CEST，用HS反转脉冲代替传统的饱和 脉冲，并改变每单位时间的HS脉冲数，以在两次扫描中引起不同的CEST效应，但不同 HS脉冲幅度保持恒定的平均饱和功率，使背景直接饱和 和MT是相同的。两次扫描相减将CEST效应从背景信号中分离出来，这解决了 常规CEST成像中的非特异性、B1和B0不均质性的挑战性问题。穿过 这三个目标，我们将提供一种独特的MRI方法来测量胆碱磷脂及其代谢 具有高灵敏度，这将允许对肿瘤进行单独的假设驱动的临床前和临床研究。

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.