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: 7017512
• 负责人: WEINIAN SHOU
• 金额: $ 28.12万
• 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/7017512
• 关键词: androgen binding protein; androgen receptor; apoptosis; biological signal transduction; cell line; congenital reproductive system disorder; disease /disorder etiology; disease /disorder model; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; male; male reproductive system; mesenchyme; organ culture; peptidylprolyl isomerase; protein protein interaction; protein structure function; reproductive development; testosterone

DESCRIPTION (provided by applicant): 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 protein, FKBP52, is involved in the etiology of hypospadias. FKBP52 is also known as a steroid receptor associated-tetratricorpeptide 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-deficient males 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.

描述(申请人提供)：尿道下裂是一种常见的出生缺陷。虽然其病因尚不清楚，但通常认为是雄激素不敏感引起的。1997年，美国疾病控制和预防中心(CDC)发布的报告显示，从1968年到1993年，美国的尿道下裂病例几乎增长了100%。有人认为，内分泌干扰剂对环境的污染可能是导致此次疫情的原因之一。尽管其发病率很高，但在不到2%的尿道下裂患者中发现了雄激素受体(AR)或5D-还原酶突变，这表明雄激素信号或代谢途径中的多个靶点参与了尿道下裂的发生。手术修复是治疗尿道下裂的唯一方法。由于缺乏尿路下裂的动物模型，限制了我们确定该病发病机制的努力，以及新疗法的开发。在这个应用中，我们将调查我们的发现，FK506结合蛋白，FKBP52，参与了尿道下裂的病因学。FKBP52也被称为类固醇受体相关四肽重复结构域蛋白(SRA-TPR)，因为它能够通过与热休克蛋白90(Hsp90)的直接相互作用进入类固醇受体的异源复合体。FKBP52是几种SRA-TPR之一，存在于AR复合体、孕激素受体(PR)和糖皮质激素受体(GR)复合体中。在GR系统中，已知FKBP52可以增加激素的结合亲和力，而FKBP51(一种密切相关的SRA-TPR)可以减弱(但不是取消)这一功能。为了研究FKBP52在体内的作用，我们产生了FKBP52缺陷小鼠。值得注意的是，FKBP52缺乏的男性会导致严重的尿道下裂，外显率为100%。我们在胚胎和成体阶段的初步形态和组织学特征揭示了FKBP52在雄激素介导的男性生殖器发育中的重要作用。因此，这项提议将检验FKBP52是配体诱导的雄激素受体作用的关键调节因子，并对男性尿道和生殖器发育至关重要的假设。我们将通过以下方式验证这一假说：1)我们将确定腹侧尿道上皮关闭和男性生殖器发育的发育机制；2)我们将在细胞和分子水平上确定FKBP52在雄激素受体信号转导中的作用；3)我们将利用小鼠遗传工具研究FKBP51对AR功能和尿道下裂发育的贡献。