MRI of Mobile Protein and Immobile Metabolite via Magnetization Rotation Transfer

描述(申请人提供)：本提案的目标是开发和评估一种新的磁共振成像(MRI)技术，磁化旋转转移(MRT)，它可以同时提供组织内两种类型的分子变化的信息，并可用于定量组织表征。MRT可以定位可移动蛋白和特定固定代谢物在组织内的变化。反映MRT的图像可用于各种病理的诊断和评估，并将立即应用于实体肿瘤的评估。传统的溶质分子与水之间的磁化传递(MT)已经被广泛地用来报告非共振制备射频脉冲对水的影响，但由于脂质的存在、不对称背景线形和重叠共振的存在，识别生物组织中特定的分子MT效应一直是具有挑战性的。该建议旨在通过开发MT成像的变体MRT来解决这些缺陷，与传统的MT成像相比，MRT是一种更健壮的方法，因为它可以分离出更具体的MT效应，并且不易受到伪影和实验变量的影响。MRT涉及用脉冲MT序列在不同的照射翻转角度但相同的平均功率下采集的两个信号的相减。通过这一策略，具有极短T2的自旋(例如大分子)、与水的相对较快的交换速率(例如胺质子)以及非共振辐射的直接水饱和效应将被消除。因此，MRT图像只对与水的交换速率相对较慢的自旋敏感(例如，酰胺、质子或原子核Overhauser增强)。在我们之前的研究中，我们发现了两个特别的对比(相对于水共振的MRT效应在3.5ppm和-1.6ppm)是特别令人感兴趣的。我们假设：(1)MRT(3.5)反映了组织中可移动的蛋白质含量，比传统的APT更具特异性；(2)MT(-1.6)反映的是主要与限制性胆碱化合物相对应的固定代谢产物。对流动蛋白含量和含胆碱代谢物的非侵入性测量为组织定性以及监测癌症状态提供了一种独特的方法。在目标1中，我们将进一步开发和优化实用的MRT成像方法。AIMS 2和3将确定MRT(3.5)对肿瘤中可移动蛋白的特异性，并通过生化和蛋白质组学分析探讨MRT(-1.6)来自固定代谢物的来源。总体而言，这项拟议的研究将扩展无处不在的成像技术MRI的能力，以提供一种以新方式定量描述组织特定分子含量的方法，并可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.