Sensitive and Specific detection of BAT Tissue and Activity by Magnetic Resonance with Hyperpolarized Xe-129

 描述(申请人提供)：棕色脂肪组织(BAT)是一种存在于所有哺乳动物中的组织，专门用于非颤抖产热(NST)。最近的研究表明，BAT对人体能量平衡和血糖稳态具有调节作用，可能对肥胖和糖尿病具有保护作用。随着触发蝙蝠分化和活性的生化机制的发现，以及针对这种组织的新的治疗方法的开发，对蝙蝠组织和产热活性的非侵入性检测仍然具有挑战性。在超重和肥胖的动物和人类身上尤其难以检测到蝙蝠，因为在这些动物和人类中，蝙蝠组织存在，但代谢不活跃。此外，通过测量组织对潜在NST底物的摄取或通过测量可能与NST相关的生理变化，只能间接非侵入性地检测BAT的生热活性。对啮齿动物和人类的超极化129Xe气体(HP 129Xe)的初步磁共振研究表明，刺激NST会导致吸入的HP 129Xe气体选择性地向下游积聚到蝙蝠体内，无论刺激NST之后是否伴随着BAT的激活。同时，Xe在BAT中溶解时，其化学位移对温度的依赖关系可用于实时、高精度地直接测量BAT的温度和生热活性。这项拟议工作的目的是验证这种新的方法，用于非侵入性检测棕色脂肪组织并表征其功能。具体地说，第一个目标是确定129Xe MRI是否能够以组织学为基本事实，在不同BAT功能状态的动物身上，以更高的准确性和灵敏度量化BAT组织体积和质量，而不是18FDG-PET、1H MRI和对比超声等传统成像方法。在第二个目标中，将通过直接与不同生热能力的小鼠动物模型中的温度探头进行比较，来评估BAT的HP氙气磁共振测温的绝对准确性。在第三个目标中，将评估HP 129Xe MR相对于18FDG-PET的敏感性和特异性。HP129Xe MR对BAT的可靠识别，加上对其生热活性的直接测量，将加强旨在了解调控该组织发育、分化和激活的主要因素的临床前研究的成功。在临床研究环境中，这样的工具将使我们能够在更多的人类受试者中正确评估正常和异常的BAT功能，并确定专门针对这一组织的新的抗肥胖和抗糖尿病疗法的疗效。

 DESCRIPTION (provided by applicant): Brown Adipose Tissue (BAT) is a tissue present in all mammals and is specialized for non-shivering thermogenesis (NST). Recent studies showed that BAT plays a regulatory role in human energy balance and glucose homeostasis and may have a protective role against obesity and diabetes. As the biochemical mechanisms that trigger the differentiation and the activity of BAT are being discovered, and as new therapeutic treatments that specifically target this tissue are being developed, non-invasive detection of BAT tissue and thermogenic activity remains challenging. BAT is especially difficult to detect in animals and in humans that are overweight and obese, in which this tissue is present but metabolically inactive. In addition, BAT thermogenic activity can be detected non-invasively only indirectly, either through measurement of tissue uptake of potential NST substrates or through measurements of physiological changes that may correlate with NST. Preliminary magnetic resonance studies with HyperPolarized 129Xe gas (HP 129Xe) in rodents and humans show that stimulation of NST leads to a selective downstream accumulation of inhaled HP 129Xe gas into BAT, whether or not stimulation of NST is followed by BAT activation. At the same time, when xenon dissolves in BAT, the temperature dependence of its chemical shift can be used to directly measure BAT temperature and thermogenic activity in real time and with high accuracy. The objective of the proposed work is to validate this novel methodology for the non-invasive detection of brown adipose tissue and for the characterization of its function. Specifically, the first aim will establish whether 129Xe MRI can quantify BAT tissue volume and mass with better accuracy and sensitivity than conventional imaging methodologies like 18FDG-PET, 1H MRI, and contrast ultrasound in animals with different BAT functional states, while using histology as ground truth. In the second aim, absolute accuracy of HP xenon MR thermometry of BAT will be assessed in vivo by direct comparison with temperature probes in murine animal models with different thermogenic capacity. With the third aim, sensitivity and specificity of HP 129Xe MR with respect to 18FDG-PET will be assessed in humans. Reliable identification of BAT by HP129Xe MR, coupled with direct measurement of its thermogenic activity, will enhance the success of preclinical research studies aiming at understanding the primary factors that regulate the development, the differentiation and the activation of this tissue. In the clinical research setting, such a tool will allow us to correctly assess, in a larger number of human subjects, normal and abnormal BAT function, and to determine the efficacy of new anti-obesity and anti-diabetes therapies that specifically target this tissue.