Physiological Roles of Receptor-Associated Immunophilins

描述（由申请人提供）：本项目的目的是了解类固醇激素受体相关亲免疫素（FKBP 51和FKBP 52）在糖皮质激素受体（GR）介导的生理过程中的作用，并评估FKBP 51和FKBP 52缺失小鼠作为模型系统研究已知与糖皮质激素反应改变相关的人类疾病的可能性。首先，将使用各种组织化学和免疫组织化学染色方法在小鼠中评估FKBP 51和FKBP 52基因表达模式。接下来，将通过从FKBP 51和FKBP 52缺失小鼠分离的肝细胞中的GR配体结合和GR介导的基因表达来评估缺乏FKBP 51和/或FKBP 52基因的小鼠中改变的GR应答。最后，将在FKBP 51和FKBP 52缺失小鼠中评估通常响应于皮质醇过少和/或皮质醇过多（例如躯干肥胖）而改变的各种生理参数。FKBP 51过表达已归因于松鼠猴中的皮质醇抵抗。因此，这些研究也有助于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.