Role of FKBP52 in androgen signaling and hypospadias

FKBP52 在雄激素信号传导和尿道下裂中的作用

• 批准号: 7339838
• 负责人: WEINIAN SHOU
• 金额: $ 25.54万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339838
• 关键词: Adult; Affect; Affinity; Androgen Receptor; Androgens; Animal Model; Animals; Apoptosis; Attenuated; Binding; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Closure; Complex; Congenital Abnormality; DNA Binding; Data; Development; Disease; Disease Outbreaks; Embryo; Endocrine Disruptors; Environmental Pollution; Epithelial; Epithelium; Etiology; Exhibits; FK506 binding protein 5; Fibroblasts; Funding; Genetic; Genetic Transcription; Genital system; Glucocorticoid Receptor; Goals; Heat-Shock Proteins 90; Heat-Shock Response; High Prevalence; Hormones; Hypospadias; Immunohistochemistry; In Situ Hybridization; In Vitro; Ligands; Link; Male Genital Organs; Mediating; Mesenchymal; Mesenchyme; Metabolism; Mind; Molecular; Morphogenesis; Mus; Mutation; Nuclear Translocation; Operative Surgical Procedures; Organ Culture Techniques; Organogenesis; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Population; Progesterone; Progesterone Receptors; Property; Proteins; Receptor Signaling; Regulation; Relative (related person); Report (document); Research Personnel; Role; Signal Transduction; Staging; Steroid Receptors; Steroids; System; Tacrolimus Binding Proteins; Tertiary Protein Structure; Testing; Testosterone; Tissues; Transactivation; Urethra; base; concept; in vivo; male; programs; promoter; protein structure; receptor; receptor expression; receptor function; repaired; research study; tacrolimus binding protein 4; tool

Hypospadias is a common birth defect. Although its etiology is unknown, it is generally considered to arise from androgen insensitivity. In 1997, the Center for Disease Control and Prevention (CDC) released reports documenting an increase of almost 100% in hypospadias cases in the US from 1968 to 1993. It was suggested that environmental contamination by endocrine disrupting agents might have contributed to this outbreak. In spite of its high prevalence, mutations in androgen receptor (AR) or 5D-reductase have been found in less than 2% of the hypospadias patient population, suggesting that multiple targets in the pathways of androgen signaling or metabolism contribute to hypospadias. Surgical repair is the only treatment for hypospadias. Lack of an animal model for hypospadias has limited our efforts to identify the pathogenesis of the disease, as well as development of new therapies. In this application, we will investigate our discovery that the FK506-binding rjrotein, FKBP52, is involved in the etiology of hypospadias. FKBP52 is also known as a steroid receptor associated-tetratricorjeptide repeat domain protein (SRA-TPR) based on its ability to enter into heterocomplexes with steroid receptors via a direct interaction with heat shock protein 90 (Hsp90). FKBP52 is one of several SRA-TPRs and is found in the AR complex, as well as in progesterone receptor (PR) and glucocorticoid receptor (GR) complexes. In the GR system, FKBP52 is known to increase the binding affinity for hormone, while FKBP51 (a closely-related SRA-TPR) serves to attenuate (but not abolish) this function. In an effort to study the role of FKBP52 in vivo, we generated FKBP52-deficient mice. Strikingly, FKBP52-deficientmales give rise to severe hypospadias with 100% penetrance. Our initial morphological and histological characterization at both embryonic and adult stages revealed an essential role of FKBP52 in androgen-mediated male genital development.Accordingly,this proposal will test the hypothesis that FKBP52 is a key regulator of ligand-induced androgen receptor action and is critical to male urethral and genital development. We will test this hypothesis in the following ways: 1)we will determine the developmental mechanism of ventral urethral epithelium closure and male genital development; 2) we will determine the role of FKBP52 in androgen receptor signaling at both the cellular and molecular level; 3) we will study the contribution of FKBP51 to AR function and the development of hypospadias using mouse genetic tools.

尿道下裂是一种常见的出生缺陷。虽然其病因不明，但一般认为是由于 雄激素不敏感。 1997年，美国疾病控制与预防中心（CDC）发布报告，记录了 从 1968 年到 1993 年，美国尿道下裂病例几乎增加了 100%。有人建议，环境因素 内分泌干​​扰物的污染可能是此次疫情爆发的原因之一。尽管其高 患病率中，不到 2% 的人发现雄激素受体 (AR) 或 5D 还原酶突变 尿道下裂患者群体，表明雄激素信号通路中的多个靶点或 新陈代谢会导致尿道下裂。手术修复是尿道下裂的唯一治疗方法。缺少动物 尿道下裂模型限制了我们确定该疾病发病机制以及该疾病发展的努力 新疗法。在此应用中，我们将研究我们的发现，即 FK506 结合蛋白 FKBP52 是 参与尿道下裂的病因学。 FKBP52 也称为类固醇受体相关四三肽 重复结构域蛋白（SRA-TPR）基于其通过类固醇受体进入异质复合物的能力 与热休克蛋白 90 (Hsp90) 直接相互作用。 FKBP52 是几种 SRA-TPR 之一，存在于 AR 中 复合物，以及黄体酮受体 (PR) 和糖皮质激素受体 (GR) 复合物。在GR系统中， FKBP52 已知可增加激素的结合亲和力，而 FKBP51（一种密切相关的 SRA-TPR）可增强激素的结合亲和力。 减弱（但不是消除）这种功能。为了研究 FKBP52 在体内的作用，我们生成了 FKBP52 缺陷小鼠。引人注目的是，FKBP52 缺陷的男性会出现外显率 100% 的严重尿道下裂。 我们在胚胎和成体阶段的最初形态学和组织学特征揭示了一个重要的 FKBP52在雄激素介导的男性生殖器发育中的作用。因此，本提案将检验该假设 FKBP52 是配体诱导的雄激素受体作用的关键调节因子，对男性尿道和生殖器至关重要 发展。我们将通过以下方式检验这个假设：1）我们将确定发展 腹侧尿道上皮闭合与男性生殖器发育的机制； 2）我们将确定角色 FKBP52 在细胞和分子水平上参与雄激素受体信号传导； 3）我们将研究的贡献 使用小鼠遗传工具，FKBP51 影响 AR 功能和尿道下裂的发展。