Enabling accurate identification and quantification of brown adipose tissue mass by xenon enhanced computed tomography

通过氙增强计算机断层扫描能够准确识别和量化棕色脂肪组织块

• 批准号: 10052750
• 负责人: Rosa Tamara Branca
• 金额: $ 49.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10052750
• 关键词: Address; Adipose tissue; Adopted; Adult; Affect; Animal Model; Biopsy; Blood flow; Brown Fat; Cardiovascular Diseases; Clinical; Computational Technique; Contrast Media; Coupled; Detection; Development; Diabetes Mellitus; Dose; Energy Intake; Energy Metabolism; Epidemic; Epidemiology; Evolution; Gases; Goals; Gold; Growth; Health Care Costs; Histology; Human; Human Biology; Hydration status; Hypertrophy; Imaging Techniques; Inhalation; Insulin; Insulin Resistance; Intervention; Knowledge; Lead; Longitudinal Studies; Measurement; Measures; Methods; Monitor; Morphology; National Institute of Diabetes and Digestive and Kidney Diseases; Needle biopsy procedure; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Overweight; PET/CT scan; Pathogenesis; Phenotype; Play; Population; Positron-Emission Tomography; Prevalence; Protocols documentation; Publishing; Radiation exposure; Reproducibility; Research Personnel; Research Project Grants; Research Proposals; Research Subjects; Risk Factors; Role; Sensitivity and Specificity; Specificity; Stimulus; Target Populations; Techniques; Therapeutic Intervention; Thermogenesis; Thinness; Tissue Differentiation; Tissues; Translating; Validation; Work; X-Ray Computed Tomography; Xenon; base; blood glucose regulation; diabetes mellitus therapy; energy balance; fluorodeoxyglucose; glucose uptake; head-to-head comparison; imaging approach; insight; lipophilicity; low dose computed tomography; new therapeutic target; nonhuman primate; novel strategies; novel therapeutic intervention; novel therapeutics; obesity treatment; phantom model; pre-clinical; reconstruction; research study; response; sex; targeted treatment; tomography; tool; uptake

PROJECT SUMMARY / ABSTRACT In the US, more than 36% of the population is obese and 9.4% has diabetes, most of which is type-2 diabetes driven by obesity-associated insulin resistance. Current anti-obesity strategies have been proven to be largely inadequate, and new-targeted therapies are desperately needed to stop this epidemic. At the fundamental level, obesity results from the imbalance between energy intake and energy expenditure. The latter can be regulated by the activity of brown adipose tissue (BAT), a tissue that plays a regulatory role not only in energy balance, but also in glucose homeostasis. As a result, new therapeutic approaches are now being devised to target BAT for the treatment of obesity and diabetes. However, a major roadblock to the development of such therapies is the ability to detect and quantify BAT mass accurately. Current techniques are either too insensitive, or lack the necessary specificity to differentiate this tissue from white adipose tissue. This is especially true in overweight/obese subjects - the target population for interventional therapies targeting BAT. The goal of the proposed research project is to develop a new imaging approach based on low-dose, xenon- enhanced CT (XECT) that can detect BAT and yield accurate measurements of its mass, independently of its activity. This proposal builds upon our preliminary results, in which we had shown that the inert and lipophilic gas xenon can be used as a CT contrast agent to detect and quantify BAT mass. Regardless of the tissue's thermogenic capacity, hydration status, and glucose uptake capacity, upon stimulation of thermogenic activity, xenon accumulates into BAT at a concentration high enough to significantly change the radiodensity of this tissue, making BAT visible in CT images. Our objectives in this application are: a) to characterize xenon uptake dynamics in BAT as a function of tissue hydration and thermogenic potency in lean and obese non human primates animal models; b) to characterize and optimize low-dose XECT protocols for use in longitudinal studies in humans; and c) to establish that low- dose XECT can correctly identify BAT with greater sensitivity and specificity than 18F-FDG-PET/CT, the most widely used technique for measurement of BAT volume, using biopsy as ground truth. XECT will enable accurate quantification of BAT mass in the general adult human population, while providing new insights into the morphological changes that occur in this tissue during the onset of obesity. This project is expected to have a high impact; this novel approach can be easily implemented on standard PET/CT platforms and combined with other functional measures of BAT to increase their accuracy by reducing partial volume effects. Accurate quantification of BAT mass and activity is expected to lead to a better understanding of the growth, evolution, and remodeling of this tissue resulting from various stimuli and conditions.

项目概要/摘要 在美国，超过 36% 的人口肥胖，9.4% 的人患有糖尿病，其中大部分是 2 型糖尿病 由肥胖相关的胰岛素抵抗驱动。目前的抗肥胖策略已被证明在很大程度上是 不足，迫切需要新的靶向疗法来阻止这种流行病。从根本上来说 一般来说，肥胖是由于能量摄入和能量消耗不平衡造成的。后者可以是 受棕色脂肪组织 (BAT) 活性的调节，该组织不仅在能量方面发挥调节作用 平衡，还包括葡萄糖稳态。因此，现在正在设计新的治疗方法 治疗肥胖和糖尿病的目标 BAT。然而，此类技术发展的一个主要障碍是 疗法的关键是准确检测和量化 BAT 质量的能力。目前的技术要么是 不敏感，或缺乏区分该组织与白色脂肪组织的必要特异性。这是 尤其是超重/肥胖受试者——BAT 介入治疗的目标人群。 拟议研究项目的目标是开发一种基于低剂量氙气的新成像方法 增强 CT (XECT) 可以检测 BAT 并准确测量其质量，而不受其影响 活动。该提议建立在我们的初步结果的基础上，其中我们表明惰性和亲脂性 氙气可用作 CT 造影剂来检测和量化 BAT 质量。与组织的情况无关 生热活性刺激后的生热能力、水合状态和葡萄糖摄取能力， 氙以足够高的浓度积聚到 BAT 中，足以显着改变其放射密度 组织，使 BAT 在 CT 图像中可见。 我们在此应用中的目标是：a) 将 BAT 中的氙吸收动态特征描述为组织的函数 瘦和肥胖非人类灵长类动物模型中的水合作用和产热效力； b) 表征 并优化用于人类纵向研究的低剂量 XECT 方案； c）建立低 剂量 XECT 可以正确识别 BAT，其灵敏度和特异性比 18F-FDG-PET/CT 更高，是最 广泛使用的 BAT 体积测量技术，使用活检作为基本事实。 XECT 将能够准确量化一般成年人群中的 BAT 质量，同时提供 对肥胖发作期间该组织中发生的形态变化的新见解。这个项目是 预计会产生重大影响；这种新颖的方法可以在标准 PET/CT 平台上轻松实施 并与BAT的其他功能措施相结合，通过减少部分体积来提高其准确性 影响。 BAT 质量和活性的准确量化预计将有助于更好地了解 各种刺激和条件导致该组织的生长、进化和重塑。