Novel Magnetic Resonance Approach to Detect BAT Distribution and Temperature

描述（由申请人提供）：最近在人类中检测到棕色脂肪组织（BAT），表明如果BAT在人类中可以发挥与在动物中调节体重相同的作用，则肥胖控制的策略完全不同。可以说，回答这个问题的最大障碍是缺乏一种非侵入性的方法来检测BAT在人体中的存在和活动。目前可用于检测人类BAT的唯一技术（18 FDG-PET）容易出现假阴性，受到高扫描-再扫描变异性的影响，并导致显著的辐射暴露，这限制了对同一受试者进行测试新药疗效所需的重复研究。这项研究的长期目标是开发一种基于MRI的非侵入性方法，可以检测人体中BAT的存在和活动。本申请的目的是在临床前开发和优化该方法，然后通过与组织学和更成熟的18FDG-PET扫描进行比较来验证该方法。 所提出的方法使用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iZQC），该方法利用BAT和白色脂肪组织（WAT）之间的结构差异。中心假设是，所提出的方法是敏感的组织微观结构，可以区分BAT仓库从WAT。此外，由于该方法对BAT温度敏感，因此可用于监测组织活性。这一假设是根据研究者实验室的初步结果制定的，该实验室在NMR光谱中确定了BAT的标记物，该标记物来自相距100微米的自旋之间的iZQC信号。在强有力的初步数据的指导下，该研究将通过追求两个具体目标来测试中心假设：1）开发，优化和验证这种用于小鼠体内BAT定位的方法; 2）优化和加速BAT温度测量以监测小鼠中的BAT活动。所提出的方法是创新的，因为它利用了iZQC对组织结构的独特敏感性来检测与其他组织混合的小BAT库的存在，以及其对温度的敏感性来监测BAT活性。这项拟议中的研究意义重大，因为增加体内测量BAT质量和BAT活性的能力将使人们更好地了解BAT在生理学中的作用及其作为治疗肥胖症的治疗靶点的潜力。该方法是非侵入性的;信号是内在的，甚至不需要造影剂管理。因此，它允许对同一受试者进行重复扫描，这对于测试为增加BAT组织质量或增强BAT活性而开发的新药的疗效至关重要。 公共卫生相关性：该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BAT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卫生有关，因为用于非侵入性检测BAT的新工具将显示BAT发生与肥胖之间的联系，并最终加速开发更好的肥胖治疗方法的过程。

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.