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

使用新型正电子发射断层扫描放射性配体直接测量肥胖症中 11β-羟基类固醇脱氢酶 1 型 (11β-HSD1) 酶水平

• 批准号: 10426245
• 负责人: Jason Bini
• 金额: $ 15.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426245
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Adipocytes; Adipose tissue; Affect; Animals; Area; Award; Binding; Biological Assay; Body Weight; Body Weight decreased; Brain; Clinical Endocrinology; Communities; Conflict (Psychology); Cortisone; Cushing Syndrome; Data; Deposition; Dose; Education; Endocrinology; Enzymes; Functional disorder; Gluconeogenesis; Glucose; Goals; Health; Hepatic Tissue; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hyperglycemia; Image; Imaging Techniques; Impairment; In Vitro; Individual; Insulin; Insulin Resistance; K-Series Research Career Programs; Kinetics; Knock-out; Knowledge; Lead; Learning; Liver; Measurement; Measures; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Modeling; Mus; Muscle; Myoblasts; NADH dehydrogenase (ubiquinone); Non obese; Obesity; Pancreas; Pharmacology; Phenotype; Physiology; Plasma; Population; Positron; Positron-Emission Tomography; Pre-Clinical Model; Prevalence; Publishing; Quality of life; Rat Strains; Rattus; Reporting; Research; Research Design; Research Methodology; Research Personnel; Research Training; Resistance; Rodent; Role; Skeletal Muscle; Societies; Steroids; Structure; Thinness; Tissues; Training; Training Programs; United States; Visceral; Weight; Weight Gain; adipocyte differentiation; age related; base; career; design; dietary control; effective therapy; experience; fasting glucose; hepatic vein; human subject; imaging study; improved; in vivo; innovation; insulin secretion; insulin sensitivity; non-diabetic; novel; obese person; phase II trial; programs; radioligand; response; skills; stable isotope; steroid hormone; subcutaneous; tool; treatment strategy; uptake; urinary; whole body imaging

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.

项目摘要 美国人口的肥胖症患病率超过30％，易于大部分 人口为代谢疾病。皮质醇是一种类固醇马酮，在肥胖症中至关重要，因为它是 负责刺激肝脏中的谷胱甘肽生成并促进脂肪细胞分化和成熟。 皮质醇通过细胞内酶11β-羟基固醇脱氢酶1型从可可素激活（11β-） HSD1）。 该提案的总体目的是检查全身11β-HSD1酶分布水平 正常的生理学以及使用新颖的18F-FMOZAT的体重增加，胰岛素抵抗和肥胖症的响应 啮齿动物和人类种群中的PET放射性物体。全身宠物成像可以直接测量 11β-HSD1的分布允许使用尿路或血浆皮质醇与常规方法进行比较 瘦肉和非糖尿病肥胖人物中的代谢产物。我们提出了肥胖的Zucker Fatty（ZF）大鼠 模型将允许在进展过程中在各个时间内在各个时间内直接在体内PET成像 肥胖（目标1）。我们还建议检查瘦和非糖尿病肥胖个体中的11β-HSD1水平 18F-FMOZAT PET评估全身11β-HSD1酶水平的组织特异性变异性，并比较 这些新型直接测量使用当前方法使用皮质醇的泌尿代谢物（AIM 2）。 该K01指导职业发展奖中描述的研究和培训计划 申请将为候选人提供必要的技能和经验，以成为独立的 内分泌学领域的研究者（肥胖）。在领域领导专家的精神状态下 内分泌学和肥胖以及宠物成像，拟议的目标将负担在设计，行为和 分析新型翻译宠物成像技术，以唯一应用于代谢综合征 内分泌学，例如肥胖。为了实现这一目标，候选人提出了进一步的培训 三个主要领域1）在临床内分泌学（肥胖）研究中建立专业知识2）接受教育 肥胖症的病理生理学和3）继续增强我对尖端全身宠物的了解 成像。 该奖项提供的机会将使候选人能够踏上全面的， 结构化的5年培训和研究计划旨在培养创新专家 内分泌研究方法是独立研究者的职业。