Physiological Roles of Receptor-Associated Immunophilins

描述(由申请人提供)：本项目的目标是了解类固醇激素受体相关免疫亲和素(FKBP51和FKBP52)在糖皮质激素受体(GR)介导的生理过程中的作用，并评估FKBP51和FKBP52缺失小鼠作为模型系统的可能性，以研究与糖皮质激素反应改变相关的已知人类疾病。首先，将使用各种组织化学和免疫组织化学方法评估FKBP51和FKBP52基因在小鼠中的表达模式。接下来，从FKBP51和FKBP52缺失小鼠分离的肝细胞中，通过GR配体结合和GR介导的基因表达来评估缺失FKBP51和/或FKBP52基因的小鼠的GR反应改变。最后，将在FKBP51和FKBP52基因缺失的小鼠中评估通常因皮质醇过低和/或过高而改变的各种生理参数(例如，躯干肥胖)。FKBP51的过度表达被归因于松鼠猴子对皮质醇的抵抗。因此，这些研究还可以帮助药物更好地了解患者对皮质类固醇药物产生耐药性的机制。

DESCRIPTION (provided by applicant): The goals of this project are to understand roles of the steroid hormone receptor-associated immunophilins (FKBP51 and FKBP52) in glucocorticoid receptor (GR)-mediated physiological processes, and to assess the likelihood that the FKBP51 and FKBP52 null mice could serve as model systems for the study of known human diseases associated with altered glucocorticoid responses. First, the FKBP51 and FKBP52 gene expression patterns will be assessed in mice using various histochemical and immunohistochemical staining methods. Next, an altered GR response in mice lacking the FKBP51 and/or FKBP52 genes will be demonstrated as assessed by GR ligand binding and GR-mediated gene expression in hepatocytes isolated from FKBP51 and FKBP52 null mice. Finally, various physiological parameters that are typically altered in response to hypo- and/or hypercortisolism (e.g. truncal obesity) will be assessed in FKBP51 and FKBP52 null mice. FKBP51 overexpression has been attributed to cortisol resistance in squirrel monkeys. Thus, these studies could also contribute drugs to a better understanding of the mechanism by which patients acquire resistance to corticosteroid drugs.