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 美国人口中肥胖症的患病率超过30%，导致很大一部分肥胖症。 代谢性疾病。皮质醇，一种类固醇激素，在肥胖中至关重要，因为它是 负责刺激肝脏中的脂肪生成并促进脂肪细胞分化和成熟。 皮质醇由可的松通过细胞内酶11β-羟基类固醇脱氢酶1型（11β-羟基类固醇脱氢酶）活化。 HSD1）。 该提案的总体目标是检查在治疗期间全身11β-HSD 1酶分布水平。 正常生理学和对体重增加、胰岛素抵抗和肥胖的反应 啮齿动物和人类群体中的PET放射性配体。全身PET成像可以直接测量 11β-HSD 1的分布允许与使用尿或血浆皮质醇的常规方法进行比较 在瘦的和非糖尿病的肥胖人类个体中的代谢物。我们提出了一个肥胖的Zucker脂肪（ZF）大鼠 该模型将允许直接体内PET成像的11β-HSD 1水平在各种组织的进展， 肥胖（目标1）。我们还建议检测11β-HSD 1在瘦和非糖尿病肥胖个体中的水平， 18F-FMOZAT PET评估全身11β-HSD 1酶水平的组织特异性变异性，并比较 这些新的直接措施与目前的方法，使用尿代谢产物的皮质醇（目标2）。 K 01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，成为独立的 内分泌学（肥胖症）领域的研究者。在外地领先专家的指导下， 内分泌学和肥胖症，以及PET成像，拟议的目标将提供培训的设计，进行， 分析新的平移PET成像技术，以独特地应用于代谢综合征， 内分泌学，如肥胖症。为了实现这一目标，候选人提议接受以下方面的进一步培训： 三个主要领域1）建立临床内分泌学（肥胖）研究的专业知识2）接受教育， 肥胖的病理生理学和3）继续提高我的知识的尖端全身PET 显像 该奖项提供的机会将使候选人能够开展全面， 结构化的5年培训和研究计划，旨在发展创新的专业知识 内分泌学研究方法走向职业生涯作为一个独立的调查员。