Functional Dissection of Glucocorticoid Action in Metabolic Disease

糖皮质激素在代谢疾病中作用的功能剖析

• 批准号: 8281496
• 负责人: Charles A Harris
• 金额: $ 8.1万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281496
• 关键词: Address; Adipocytes; Adipose tissue; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Blood Pressure; Body fat; Bone Density; Brain; CRH gene; Cells; Central obesity; Clinical; Complex; Cushingoid habitus; Development; Diabetes Mellitus; Diet; Dimerization; Disease; Dissection; Doctor of Philosophy; Endocrine; Endocrinologist; Etiology; Fatty acid glycerol esters; Fibroblasts; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Hypertension; In Vitro; Inflammatory; Insulin Resistance; Knockout Mice; Ligands; Light; Lipids; Liver; Mediating; Medical; Medicine; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Minor; Minority; Modeling; Modification; Molecular; Mus; Muscle; Mutation; NF-kappa B; Nuclear Hormone Receptors; Obesity; Osteoporosis; Oxidoreductase; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Physiological; Pituitary-dependent Cushing' s disease; Production; Property; Receptor Signaling; Regulatory Element; Repression; Research; Research Personnel; Role; Scientist; Serum; Signal Transduction; Testing; Tissues; Training; Training Programs; Transactivation; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; Universities; Washington; Wild Type Mouse; Work; adipocyte differentiation; blood glucose regulation; bone; career; feeding; in vivo; interest; lipid biosynthesis; muscle form; programs; promoter; receptor

DESCRIPTION (provided by applicant): Dr. Charles Harris is an MD/PhD trained endocrinologist with a strong interest in metabolism. Dr. Harris's development as a physician scientist was nurtured as a trainee in Washington University's Medical Scientist Training Program. His interest in glucocorticoids (GCs) was sparked as a clinical endocrine fellow seeing patients with Cushing's disease, a state of GC excess. These patients suffer from central obesity, diabetes, hypertension, osteoporosis, and CNS changes. Metabolic syndrome (MS) may also be the result of excess GC signaling, but restricted to adipose tissue. The long-term goals of Dr. Harris's work is to understand the molecular mechanisms for these effects of GCs on adipose, muscle, liver, bone and brain. GCs bind to the glucocorticoid receptor (GR). GR, a nuclear hormone receptor, activates transcription of a number of genes with GRE regulatory elements. In addition, GR inhibits transcription by tethering transcriptional complexes such as AP-1 and NF-kB. A particular mutation of GR, GRdim is of interest because transactivation is lost for the majority of target genes. A minority of GR targets are still activated by GRdim pointing to a minor subset of GR dimerization-independent target genes. Dr. Harris will dissect the metabolic effects of GCs in vitro and in vivo using cells and mice harboring the GR mutation, GRdim. In this manner he will be able to determine the physiological significance of the GR dimerization-dependent targets. In addition, Dr. Harris will further address the role of GR action in adipose tissue by creating an adipose-specific GR null mouse. Aim 1: To identify the mechanisms of glucocorticoid-mediated adipogenesis and insulin resistance in adipocytes. Aim 2: To determine if the metabolic derangements induced by excess glucocorticoids are mediated by GR dimerization-dependent targets or by GR action in adipose tissue. Aim 3: To determine if the obesogenic properties of a high-fat diet are mediated by GR dimerization-dependent targets and if they are mediated by GR action in adipose tissue. By completing these aims Dr. Harris will make his transition to becoming an independent physician-scientist researcher in academic medicine, his career goal. Relevance: The research will shed light on the etiology of GC-mediated adverse metabolic effects as well as the metabolic syndrome. In addition, the proposed research could point to the use of "dissociated GCs", safer anti-inflammatory medications to treat the millions of patients afflicted with inflammatory diseases.

描述（由申请人提供）： 查尔斯·哈里斯（Charles Harris）博士是一名受过医学博士/博士学位训练的内分泌学家，对代谢有浓厚的兴趣。哈里斯博士作为医师科学家的发展是在华盛顿大学医学科学家培训计划中作为学员培养的。他对糖皮质激素（GC）的兴趣被激发为临床内分泌伴侣，观察患有库欣氏病的患者，这是GC过量的状态。这些患者患有中枢性肥胖，糖尿病，高血压，骨质疏松症和中枢神经系统的变化。代谢综合征（MS）也可能是GC信号过量的结果，但仅限于脂肪组织。哈里斯博士工作的长期目标是了解GC对脂肪，肌肉，肝脏，骨骼和大脑的这些作用的分子机制。 GC与糖皮质激素受体（GR）结合。 GR是一种核激素受体，激活了具有GRE调节元件的许多基因的转录。另外，GR通过绑定转录复合物（如AP-1和NF-KB）抑制转录。 GR，GRDIM的特定突变引起了人们的关注，因为大多数靶基因都失去了反式激活。少数GR靶标仍然通过指向GR二聚化靶基因的小子集而被激活。 Harris博士将使用带有GR突变Grdim的细胞和小鼠在体外和体内剖析GCS的代谢作用。以这种方式，他将能够确定GR二聚化依赖性靶标的生理意义。此外，Harris博士将通过创建脂肪特异性的GR null小鼠在脂肪组织中进一步解决GR作用的作用。目的1：确定糖皮质激素介导的脂肪形成和胰岛素耐药性的机制。目的2：确定过量糖皮质激素诱导的代谢紊乱是由GR二聚化依赖性靶标介导的还是通过脂肪组织中的GR作用介导的。目标3：确定高脂饮食的肥胖性特性是否是由GR二聚化依赖性靶标介导的，以及它们是否是通过脂肪组织中的GR作用介导的。通过完成这些目标，哈里斯博士将过渡到成为一名独立的医生学术医学研究员，即他的职业目标。相关性：该研究将阐明GC介导的不良代谢作用以及代谢综合征的病因。此外，拟议的研究可能指出使用“解散的GC”，更安全的抗炎药来治疗数百万患有炎症性疾病的患者。