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

 描述（由申请人提供）：棕色脂肪组织（BAT）是一种存在于所有哺乳动物中的组织，专门用于非颤抖性产热（NST）。最近的研究表明，BAT在人体能量平衡和葡萄糖稳态中起着调节作用，并可能对肥胖和糖尿病具有保护作用。随着触发BAT分化和活性的生化机制的发现，以及专门针对该组织的新治疗方法的开发，BAT组织和产热活性的非侵入性检测仍然具有挑战性。BAT在超重和肥胖的动物和人类中特别难以检测，其中该组织存在但代谢不活跃。此外，BAT产热活性可以通过测量潜在NST底物的组织摄取或通过测量可能与NST相关的生理变化而仅间接地非侵入性地检测。在啮齿类动物和人类中使用超极化129氚气体（HP 129氚）进行的初步磁共振研究表明，刺激NST会导致吸入的HP 129氚气体选择性下游积聚到BAT中，无论刺激NST后是否会激活BAT。同时，当氙溶解在BAT中时，其化学位移的温度依赖性可用于真实的时间和高精度地直接测量BAT温度和生热活性。所提出的工作的目的是验证这种新的方法，棕色脂肪组织的非侵入性检测和其功能的表征。具体而言，第一个目标将确定129 FDG MRI是否可以在具有不同BAT功能状态的动物中以比传统成像方法（如18 FDG-PET，1H MRI和造影超声）更好的准确性和灵敏度量化BAT组织体积和质量，同时使用组织学作为基础事实。在第二个目标中，将通过在具有不同产热能力的小鼠动物模型中与温度探头直接比较，在体内评估BAT的HP氙MR测温的绝对准确性。第三个目标是，将在人体中评估HP 129 MR相对于18 FDG-PET的灵敏度和特异性。通过HP 129 MR对BAT进行可靠鉴定，再加上对其产热活性的直接测量，将提高临床前研究的成功率，旨在了解调节该组织发育、分化和活化的主要因素。在临床研究环境中，这种工具将使我们能够在大量人类受试者中正确评估正常和异常的BAT功能，并确定专门针对该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.