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

使用超极化 Xe-129 进行磁共振对 BAT 组织和活性进行灵敏且特异的检测

• 批准号: 9553717
• 负责人: Rosa Tamara Branca
• 金额: $ 33.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9553717
• 关键词: Adipose tissue; Affect; Animal Model; Animals; Biochemical; Biomedical Research; Blood flow; Body Temperature; Brown Fat; Chemicals; Clinical; Clinical Research; Coupled; Dependence; Detection; Development; Diabetes Mellitus; Energy Metabolism; Faculty; Fatty acid glycerol esters; Fossa; Gases; Goals; High temperature of physical object; Histology; Human; Hydration status; Image; Image Analysis; Impairment; Inhalation; Laboratories; Lipids; Magnetic Resonance; Magnetic Resonance Imaging; Mammals; Measurement; Measures; Metabolic; Metabolic Diseases; Metabolism; Methodology; Methods; Monitor; Morphology; Mus; Non-Invasive Cancer Detection; Obesity; Overweight; Pharmacology; Phenotype; Physiologic Thermoregulation; Physiological; Play; Positron-Emission Tomography; Predisposition; Process; Research; Rest; Rodent; Role; Sensitivity and Specificity; Spectrum Analysis; Supraclavicular; Temperature; Testing; Thermogenesis; Thermometry; Thinness; Time; Tissue imaging; Tissues; Ultrasonography; Validation; Weight Gain; Work; Xenon; base; blood glucose regulation; combat; design; diabetes mellitus therapy; energy balance; experimental study; fluorodeoxyglucose; glucose uptake; human subject; imaging modality; in vivo; instrumentation; insulin sensitivity; member; novel; novel therapeutics; pre-clinical; pre-clinical research; public health relevance; research study; response; success; tool; uptake

 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.

 描述（由适用提供）：棕色脂肪组织（BAT）是所有哺乳动物中都存在的组织，专门用于非动摇的热生成（NST）。最近的研究表明，BAT在人类能量平衡和葡萄糖稳态中起着调节作用，并且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正在被发现，并且随着专门针对该组织的新疗法的疗法，对蝙蝠组织和热活性活性的非侵入性检测仍然受到挑战。在超重和肥胖的动物和人类中，蝙蝠尤其难以检测，其中这种组织存在但代谢不活跃。另外，只能通过测量组织摄取潜在的NST底物的摄取或通过测量可能与NST相关的物理变化来间接检测到BAT的热活动。在啮齿动物和人类中对超极化129xE气体（HP 129XE）进行的初步磁共振研究表明，对NST的刺激会导致遗传性HP 129XE气体的选择性下游积累，无论是NST的刺激，无论是NST的刺激，都会导致BAT激活。同时，当氙气溶解在蝙蝠中时，其化学位移的温度依赖性可用于实时直接测量蝙蝠的温度和热活性，并且具有很高的精度。拟议工作的目的是验证这种新方法，以非侵入性检测棕色脂肪组织以及其功能的表征。具体而言，第一个目标将比传统的成像方法（如18FDG-PET，1H MRI，1H MRI）等传统成像方法更准确和灵敏度来确定129XE MRI是否可以以更好的精度和敏感性来量化蝙蝠组织的体积和质量。在第二个目标中，HP Xenon MR的绝对准确性将通过与热能能力不同的鼠类动物模型中的温度问题直接比较来评估体内。以第三目的，将在人类中评估HP 129XE MR相对于18FDG-PET的敏感性和特异性。 HP129XE MR对BAT的可靠鉴定，再加上其热活性的直接测量，将增强临床前研究的成功，旨在理解调节该组织的发展，分化和激活的主要因素。在临床研究环境中，这样的工具将使我们能够正确评估更多人类受试者，正常和异常的蝙蝠功能，并确定新的抗肥胖和抗糖尿病疗法的疗效，这些疗法专门针对该组织。