Role of FKBP52 in androgen signaling and hypospadias

尿道下裂是一种常见的出生缺陷。虽然其病因尚不清楚，但通常认为是由 雄激素不敏感1997年，美国疾病控制和预防中心（CDC）发布报告， 从1968年到1993年，美国尿道下裂病例几乎增加了100%。有人认为，环境 内分泌干扰物的污染可能促成了这次暴发。尽管其高 雄激素受体（AR）或5D-还原酶的突变在不到2%的人中被发现。 尿道下裂患者人群，这表明雄激素信号传导途径中的多个靶点， 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 尿道下裂的模型限制了我们确定疾病发病机制的努力， 新疗法在本申请中，我们将研究我们的发现，即FK 506结合蛋白FKBP 52是一种与FK 506结合的蛋白。 与尿道下裂的病因有关。FKBP 52也被称为类固醇受体相关的四肽 重复结构域蛋白（SRA-TPR），基于其通过一个 与热休克蛋白90（Hsp 90）直接相互作用。FKBP 52是几种SRA-TPR之一，在AR中发现， 复合物，以及孕酮受体（PR）和糖皮质激素受体（GR）复合物。在GR系统中， 已知FKBP 52增加对激素的结合亲和力，而FKBP 51（一种密切相关的SRA-TPR）用于 削弱（但不是废除）这一功能。为了研究FKBP 52在体内的作用，我们产生了 FKBP 52缺陷小鼠。值得注意的是，FKBP 52缺陷的男性会引起严重的尿道下裂，100%复发。 我们在胚胎和成体阶段的初步形态学和组织学特征显示， FKBP 52在雄激素介导的男性生殖器发育中的作用。因此，本提案将验证这一假设 FKBP 52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功能至关重要。 发展我们将通过以下方式来检验这一假设：1）我们将确定 腹侧尿道上皮关闭和男性生殖器发育的机制; 2）我们将确定 FKBP 52在细胞和分子水平上对雄激素受体信号传导的作用; 3）我们将研究FKBP 52在雄激素受体信号传导中的作用。 FKBP 51对AR功能和尿道下裂的发展使用小鼠遗传工具。

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.