MRI of Mobile Protein and Immobile Metabolite via Magnetization Rotation Transfer

描述（由申请人提供）：本提案的目的是开发和评价一种新型磁共振成像（MRI）技术，即磁化旋转转移（MRT），该技术可同时提供组织内两种类型分子变化的信息，并可用于定量组织表征。MRT可以绘制移动的蛋白质和特定的非移动的代谢物的组织内变异。反映MRT的图像可用于各种病理的诊断和评估，并将立即转化为实体瘤评估的应用。溶质分子和水之间的常规磁化转移（MT）以前已被广泛利用，以报告非共振制备射频脉冲对水的影响，但由于脂质，不对称背景线型和重叠共振的存在，在生物组织中识别特定的分子MT效应一直具有挑战性。该提案旨在通过开发MT成像的变体MRT来解决这些缺陷，与传统MT成像相比，MRT是一种更稳健的方法，因为它可以隔离更具体的MT效应，并且不太容易出现伪影和实验变量的影响。MRT涉及在不同的照射翻转角但相同的平均功率下用脉冲MT序列采集的两个信号的相减。通过这种策略，来自具有极短T2（例如大分子）的自旋、与水的相对快的交换速率（例如胺质子）以及非共振辐射的直接水饱和效应的贡献将被去除。因此，MRT图像仅对与水交换速率相对较慢的自旋敏感（例如酰胺质子或核奥弗豪泽增强）。在我们以前的研究中，我们发现了两个特别的对比（相对于水共振，3.5和-1.6 ppm的MRT效应）。我们假设：（1）MRT（3.5）反映了组织的移动的蛋白质含量，比常规APT更具特异性;（2）MT（-1.6）反映了主要对应于限制性含胆碱化合物的非移动的代谢物。移动的蛋白质含量和含胆碱代谢物的非侵入性测量为组织表征以及监测癌症状态提供了独特的方法。在目标1中，我们将进一步开发和优化实用的MRT成像方法。目的2和3将建立MRT（3.5）对肿瘤中移动的蛋白的特异性，并通过生物化学和蛋白质组学测定研究MRT（-1.6）来自非移动的代谢物的来源。总的来说，拟议的研究将扩展无处不在的成像技术MRI的能力，以提供一种以新的方式定量表征组织特定分子含量的方法，可以立即转化为临床实践。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop and evaluate a novel Magnetic Resonance Imaging (MRI) technique, Magnetization Rotation Transfer (MRT), that can provide information on two types of molecular changes within tissues simultaneously, and which may be used for quantitative tissue characterization. MRT can map variations within tissue of both mobile proteins and specific immobile metabolites. Images that reflect MRT can be used for the diagnosis and assessment of various pathologies and will have immediate translational application for the assessment of solid tumors. Conventional Magnetization Transfer (MT) between solute molecules and water has previously been extensively exploited to report the effects of off-resonance preparation radio-frequency pulses on water, but discriminating specific molecular MT effects in biological tissue has been challenging because of the presence of lipids, asymmetric background lineshapes and overlapping resonances. This proposal aims to address these deficiencies by developing a variation of MT imaging, MRT, which is a more robust method compared to conventional MT imaging because it is feasible to isolate more specific MT effects and it is less prone to artifacts and the influence of experimenta variables. MRT involves the subtraction of two signals acquired with pulsed-MT sequences at different irradiation flip angles but the same average power. By this strategy, contributions from spins with extremely short T2 (e.g. macromolecules), relatively fast exchange rates with water (e.g. amine protons), and direct water saturation effects of off-resonance irradiation will be removed. MRT images are therefore sensitive only to spins with relatively slow exchange rates with water (e.g. amide protons or Nuclear Overhauser Enhancements). In our previous studies, we have found two particular contrasts (the MRT effect at 3.5 and -1.6 ppm relative to water resonance) are of special interest. We hypothesize that: (1) MRT(3.5) reflects the mobile protein content of tissues and is more specific than the conventional APT; (2) MT(-1.6) reflects immobile metabolites corresponding mainly to restricted choline-containing compounds. Non-invasive measurements of the mobile protein content and choline-containing metabolites provide a unique approach for tissue characterization, as well as monitoring the status of cancer. In Aim 1, we will further develop and optimize practical MRT imaging methods. Aims 2 and 3 will establish the specificity of MRT(3.5) to mobile proteins in tumors, and investigate the origin of MRT(-1.6) from immobile metabolites, by biochemical and proteomic assays. Overall, the proposed research will extend the capabilities of a ubiquitous imaging technology, MRI, to provide a means for quantitatively characterizing specific molecular contents of tissues in new ways that can immediately be translated into clinical practice.