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的棕色脂肪组织（BAT）表明了一种完全不同的肥胖控制策略，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。可以说，回答这个问题的最大障碍是缺乏一种非侵入性手段来检测BAT在人类中的存在和活动。目前唯一可用于检测人类BAT （18FDG- PET）的技术容易出现假阴性，受到高扫描扫描变异性的影响，并导致显著的辐射暴露，这限制了对同一受试者进行重复研究以测试新药的功效。拟议研究的长期目标是开发一种基于非侵入性MRI的方法，可以检测人类中BAT的存在和BAT的活性。本应用程序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扫描的比较来验证该方法。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），利用BAT和白色脂肪组织（WAT）之间的结构差异。中心假设是，所提出的方法对组织微观结构敏感，可以区分BAT仓库和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。这一假设是在研究者实验室的初步结果的基础上制定的，该结果在核磁共振光谱中确定了BAT的标记，该标记来自于相隔100微米的自旋之间的iZQC信号。在强有力的初步数据指导下，本研究将通过以下两个具体目标来验证中心假设：1)开发、优化和验证该方法在小鼠体内的BAT定位；2)优化和加速BAT温度测量以监测小鼠BAT活性。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仓库的存在，以及它对温度的敏感性来监测BAT活性。这项拟议的研究意义重大，因为提高在体内测量BAT质量和BAT活性的能力，将有助于更好地了解BAT在生理学中的作用及其作为治疗肥胖的治疗靶点的潜力。该方法是非侵入性的；信号是固有的，甚至不需要造影剂。因此，它允许对同一受试者进行重复扫描，这对于测试用于增加BAT组织质量或提高BAT活性的新药的功效至关重要。

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.