Novel Magnetic Resonance Approach to Detect BAT Distribution and Temperature

描述(申请人提供)：最近在人类中检测到的棕色脂肪组织(BAT)表明了一种截然不同的肥胖控制策略，如果BAT在人类中能够发挥与在动物中一样的调节体重的作用。可以说，回答这个问题的最大障碍是缺乏一种非侵入性的手段来检测蝙蝠在人类体内的存在和活动。目前可用于检测人类BAT(18FDG-PET)的唯一技术容易出现假阴性，易受高扫描-重新扫描变异性的影响，并导致严重的辐射暴露，这限制了对同一主题的重复研究，这是测试新药疗效所必需的。这项拟议研究的长期目标是开发一种基于非侵入性核磁共振的方法，允许检测人类中蝙蝠的存在和蝙蝠的活动。该应用程序的目标是在临床前开发和优化这种方法，然后通过与组织学和更成熟的18FDG-PET扫描的比较来验证它。该方法使用了一种新的质子磁共振成像(MRI)方法(检测分子间零量子相干，或iZQCs)，该方法利用了BAT和白色脂肪组织(WAT)之间的结构差异。中心假设是，所提出的方法对组织微结构敏感，可以区分BAT和WAT。此外，由于这种方法对蝙蝠温度很敏感，可以用来监测组织的活动。这一假设是基于研究人员实验室的初步结果提出的，这些结果在核磁共振谱中确定了BAT的一个标记，该标记来自相距100微米的自旋之间的iZQC信号。在强大的初步数据的指导下，该研究将通过追求两个具体目标来检验中心假设：1)开发、优化和验证该方法用于蝙蝠在小鼠体内的定位；以及2)优化和加速蝙蝠温度测量以监测小鼠的蝙蝠活动。提出的方法是创新的，因为它利用iZQC对组织结构的独特敏感性来检测与其他组织混合的小型蝙蝠储存库的存在，并利用其对温度的敏感性来监测蝙蝠的活动。这项拟议的研究意义重大，因为提高在人体内测量蝙蝠质量和蝙蝠活动的能力将有助于更好地了解蝙蝠在生理上的作用，以及它作为治疗肥胖症靶点的潜力。这种方法是非侵入性的；信号是内在的，甚至不需要对比剂的注射。因此，它允许对同一对象进行重复扫描，这对于测试为增加蝙蝠组织质量或增强蝙蝠活动而开发的新药的有效性至关重要。 公共卫生相关性：这项拟议的研究将开发一种基于MRI的成像技术，以检测体内棕色脂肪组织(BAT)并监测其代谢状态。这种技术将为研究蝙蝠在人类中的发生并监测其随时间的代谢状态提供宝贵的工具。这项拟议的研究与公共健康相关，因为用于非侵入性检测BAT的新工具将显示BAT发生和肥胖之间的联系，并最终加速开发更好的肥胖症治疗方法的进程。

DESCRIPTION (provided by applicant): The recent detection of brown adipose tissue (BAT) in humans suggests a radically different strategy for obesity control, if BAT can play the same role in humans that it plays in animals for regulation of body weight. Arguably the largest obstacle to answering this question is the lack of a non-invasive means to detect BAT presence and activity in humans. The only technology currently available to detect human BAT (18FDG- PET) is prone to false negatives, is subject to high scan-rescan variability, and causes significant radiation exposure, which limits repeated studies on the same subject necessary to test the efficacy of new drugs. The long-term goal of the proposed research is to develop a non-invasive MRI based method that allows the detection of both BAT presence and BAT activity in humans. The objective of this application is to develop and optimize this method pre-clinically and then to validate it through comparison with histology and more established 18FDG-PET scans. The proposed approach uses a novel proton Magnetic Resonance Imaging (MRI) method (detection of intermolecular zero-quantum coherences, or iZQCs) which exploits structural differences between BAT and White Adipose Tissue (WAT). The central hypothesis is that the proposed method is sensitive to tissue microstructure and can differentiate BAT depots from WAT. Moreover, since this method is sensitive to BAT temperature it can be used to monitor tissue activity. This hypothesis has been formulated on the basis of preliminary results from the investigator's laboratory, which identify a marker for BAT in the NMR spectra that arises from the iZQC signal between spins that are 100 microns apart. Guided by strong preliminary data, the research will test the central hypothesis by pursuing two Specific Aims: 1) Develop, optimize, and validate this method for BAT localization in vivo in mice; and 2) Optimize and accelerate BAT temperature measurement to monitor BAT activity in mice. The proposed approach is innovative because it exploits the unique sensitivity of iZQC to tissue structure to detect the presence of small BAT depots that are mixed with other tissues and its sensitivity to temperature to monitor BAT activity. The proposed research is significant because increasing the ability to measure BAT mass and BAT activity in humans in vivo will allow for a better understanding of BAT's role in physiology and its potential as a therapeutic target in the treatment of obesity. The approach is noninvasive; the signal is intrinsic, and does not even require contrast agent administration. It thus allows repeated scanning on the same subject, which is critical to test the efficacy of new drugs that are developed to increase BAT tissue mass or to boost BAT activity. PUBLIC HEALTH RELEVANCE: The proposed study will develop an MRI-based imaging technique to detect Brown Adipose Tissue (BAT) in vivo and to monitor its metabolic state. Such a technique will provide an invaluable tool to study the occurrence of BAT in humans and monitor its metabolic state over time. The proposed research has relevance to public health because new tools for non-invasive detection of BAT will show the connection between BAT occurrence and obesity and ultimately accelerate the process of developing better treatments for obesity.