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

基本信息

批准号：
9149194
负责人：
Rosa Tamara Branca
金额：
$ 33.35万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/9149194
关键词：
Adipose tissue Affect Animal Model Animals Biochemical Biomedical Research Blood flow Body Temperature Breathing Brown Fat Chemicals Clinical Clinical Research Coupled Dependence Detection Development Diabetes Mellitus Energy Metabolism Faculty Fatty acid glycerol esters Fossa Gases Goals Health Heating High temperature of physical object Histology Housing Human Hydration status Image Image Analysis 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 Phenotype Physiologic Thermoregulation Physiological Play Positron-Emission Tomography Predisposition Process Research Research Design Rest Rodent Role Sensitivity and Specificity Shivering Spectrum Analysis Supraclavicular Temperature Testing Thermogenesis Thermometry Time Tissue imaging Tissues Ultrasonography Validation Weight Gain Work Xenon base blood glucose regulation combat diabetes mellitus therapy energy balance glucose uptake human subject imaging modality in vivo instrumentation insulin sensitivity member novel novel therapeutics pre-clinical pre-clinical research research study response success tool uptake

项目摘要

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（由申请人提供）：棕色脂肪组织（BAT）是存在于所有哺乳动物中的一种组织，专门用于非颤抖产热（NST）。最近的研究表明，BAT 在人体能量平衡和葡萄糖稳态中发挥着调节作用。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 的非侵入性检测已成为可能。在超重和肥胖的动物和人类中检测 BAT 的组织和产热活性仍然具有挑战性，因为这些组织存在但代谢不活跃。此外，BAT 的产热活性只能以非侵入性方式间接检测。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，对啮齿动物和人类进行的超极化 129Xe 气体 (HP 129Xe) 的初步磁共振研究表明。 NST 的刺激会导致吸入的 HP 129Xe 气体选择性地下游积累到 BAT 中，无论 NST 的刺激是否随后被 BAT 激活。同时，当氙溶解在 BAT 中时，其化学位移的温度依赖性可以是。用于直接实时、高精度测量 BAT 温度和产热活动。拟议工作的目的是验证这种非侵入性检测棕色脂肪组织及其功能表征的新方法。确定后，第一个目标是确定 129Xe MRI 是否能够以组织学为基础，比 18FDG-SpecificPET、1H MRI 和对比超声等传统成像方法更准确和灵敏地量化具有不同 BAT 功能状态的动物的 BAT 组织体积和质量在第二个目标中，将通过与具有不同产热能力的小鼠动物模型中的温度探针直接比较来评估 BAT 的 HP 氙 MR 测温的绝对准确性。 HP 129Xe MR 对 18FDG-PET 的敏感性和特异性将在人体中进行评估 HP129Xe MR 对 BAT 的可靠识别，加上其生热活性的直接测量，将提高旨在了解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正确评估大量人类受试者的正常和异常 BAT。功能，并确定专门针对该组织的新抗肥胖和抗糖尿病疗法的功效。