Direct measurement of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme levels in obesity using a novel positron emissiontomography radioligand

项目总结 美国人口中肥胖率超过30%，导致很大一部分人 人口对代谢性疾病的抵抗力。皮质醇是一种类固醇激素，在肥胖症中具有至关重要的作用。 负责刺激肝脏糖异生，促进脂肪细胞分化和成熟。 皮质醇由细胞内酶11β-羟基类固醇脱氢酶1(11β-1)激活。 HSD1)。 这项建议的总体目标是检查全身11个β-hsd1酶的分布水平。 使用新型18F-Fmozat的正常生理和对体重增加、胰岛素抵抗和肥胖的反应 啮齿动物和人类种群中的宠物放射性配基。全身PET成像可以提供一种直接测量 11β-HSD1的分布可与尿或血浆皮质醇的常规方法进行比较 瘦型肥胖者和非糖尿病肥胖者的代谢物。我们提出了一种肥胖的Zucker胖子(ZF)大鼠 模型，将允许直接体内正电子发射计算机断层扫描成像在不同组织中的11个β-hsd1水平进展到 肥胖(目标1)。我们还建议检测11个β-hsd1水平在瘦肉型和非糖尿病肥胖者中。 18F-FMOZATPET评估全身11β-HSD1酶水平的组织特异性变异，并比较 这些新的直接测量方法使用尿皮质醇的代谢物(目标2)。 K01职业发展指导奖中描述的研究和培训计划 应聘者将获得成为独立求职者所需的技能和经验。 内分泌学(肥胖症)领域的研究员。在领域领先专家的指导下， 内分泌学和肥胖学以及PET成像，拟议的目标将提供设计、实施和 新的翻译PET成像技术将独特地应用于代谢综合征的分析 内分泌学，如肥胖症。为了实现这一目标，应聘者提议在以下方面进行进一步的培训 三个主要领域1)建立临床内分泌学(肥胖症)研究的专业知识2)接受 肥胖症的病理生理学和3)继续增强我对前沿全身PET的了解 成像。 该奖项提供的机会将使候选人能够开始一项全面的、 为期5年的结构化培训和研究计划，旨在培养创新方面的专业知识 内分泌学研究方法走向独立研究人员的职业生涯。

PROJECT SUMMARY The prevalence of obesity in the United States population is over 30%, predisposing a large portion of the population to metabolic diseases. Cortisol, a steroid hormone, is of critical importance in obesity, as it is responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Cortisol is activated from cortisone by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β- HSD1). The overall aim of this proposal is to examine whole-body 11β-HSD1 enzyme distribution levels during normal physiology and in response to weight gain, insulin resistance and obesity using the novel 18F-FMOZAT PET radioligand in rodent and human populations. Whole-body PET imaging can provide a direct measure of the distribution of 11β-HSD1 allowing comparison to conventional methods using urinary or plasma cortisol metabolites in both lean and non-diabetic obese human individuals. We propose an obese Zucker fatty (ZF) rat model that will allow direct in vivo PET imaging of 11β-HSD1 levels in various tissues during progression to obesity (Aim 1). We also propose to examine 11β-HSD1 levels in lean and non-diabetic obese individuals with 18F-FMOZAT PET to assess tissue-specific variability in whole-body 11β-HSD1 enzyme levels, and compare these novel direct measures with current methods using urinary metabolites of cortisol (Aim 2). The program of research and training described in this K01 Mentored Career Development Award application will provide the candidate with the requisite skills and experience to become an independent investigator in the field of endocrinology (obesity). Under the mentorship of field-leading experts in endocrinology and obesity, and PET imaging, the proposed aims will afford training in the design, conduct and analysis of novel translational PET imaging techniques to be uniquely applied to metabolic syndromes in endocrinology, such as obesity. In pursuit of this goal, the candidate proposes to undertake further training in three primary areas 1) build expertise in clinical endocrinology (obesity) research 2) receive education in the pathophysiology of obesity and 3) continue to enhance my knowledge of cutting-edge whole-body PET imaging. The opportunities afforded by this award would enable the candidate to embark on a comprehensive, structured 5-year program of training and research designed to develop an expertise in innovative endocrinology research methods toward a career as an independent investigator.