Functional Dissection of Glucocorticoid Action in Metabolic Disease

描述(由申请人提供)： 查尔斯·哈里斯博士是一位医学博士和博士学位的内分泌学家，对新陈代谢有着浓厚的兴趣。哈里斯博士作为内科科学家的发展是作为华盛顿大学医学科学家培训计划的实习生培养起来的。他对糖皮质激素(GC)的兴趣是在一名临床内分泌研究员为库欣病患者看病时激发的，库欣病是一种GC过量状态。这些患者患有中心性肥胖、糖尿病、高血压、骨质疏松症和中枢神经系统改变。代谢综合征(MS)也可能是GC信号过多的结果，但仅限于脂肪组织。哈里斯博士工作的长期目标是了解GCs对脂肪、肌肉、肝脏、骨骼和大脑产生这些影响的分子机制。GCS与糖皮质激素受体(GR)结合。GR是一种核激素受体，通过GRE调节元件激活一些基因的转录。此外，GR通过连接AP-1和NF-kB等转录复合体来抑制转录。GR，GRdim的一种特殊突变引起了人们的兴趣，因为大多数靶基因都失去了反式激活。少数GR靶基因仍然被GRdim激活，指向GR二聚化非依赖性靶基因的一小部分。哈里斯博士将利用携带GR突变GRdim的细胞和小鼠，在体外和体内剖析GCs的代谢效应。通过这种方式，他将能够确定依赖GR二聚化的靶的生理意义。此外，哈里斯博士还将通过创造一种脂肪特异性的GR零小鼠来进一步研究GR作用在脂肪组织中的作用。目的1：探讨糖皮质激素介导的脂肪细胞成脂和胰岛素抵抗的机制。目的2：确定过量糖皮质激素引起的代谢紊乱是由GR二聚化依赖靶点还是通过脂肪组织中的GR作用介导的。目的3：确定高脂饮食的肥胖特性是否由GR二聚化依赖的靶点介导，以及它们是否由脂肪组织中的GR作用介导。通过完成这些目标，哈里斯博士将转型为学术医学领域的独立内科医生兼科学家研究员，这是他的职业目标。相关性：这项研究将阐明GC介导的不良代谢影响以及代谢综合征的病因。此外，这项拟议的研究可能指向使用“游离GC”，一种更安全的抗炎药物来治疗数百万患有炎症性疾病的患者。

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.