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.

项目总结