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，但通常被认为是由 雄激素不敏感。1997年，疾病控制和预防中心(CDC)发布了记录 从1968年到1993年，美国的尿道下裂病例几乎增加了100%。有人建议说，环境问题 内分泌干扰剂的污染可能是导致此次疫情的原因之一。尽管它的高度 患病率、雄激素受体(AR)或5D-还原酶突变在不到2%的 尿道下裂患者群体，提示雄激素信号或信号通路的多个靶点 新陈代谢导致了尿道下裂。手术修复是治疗尿道下裂的唯一方法。缺少一只动物 尿道下裂的模型限制了我们确定该病发病机制的努力，以及 新疗法。在本申请中，我们将调查我们发现的FK506结合rjrotein，FKBP52，是 与尿道下裂的病因学有关。FKBP52也被称为类固醇受体相关的四肽 重复结构域蛋白(SRA-TPR)是基于其通过一种新的蛋白质进入类固醇受体的异源复合体的能力。 与热休克蛋白90(Hsp90)直接相互作用。FKBP52是几个SRA-TPR之一，位于AR中 在孕激素受体(PR)和糖皮质激素受体(GR)复合体中也有表达。在GR系统中， 众所周知，FKBP52可以增加激素的结合亲和力，而FKBP51(一种密切相关的SRA-TPR)则起作用 削弱(但不是废除)这一功能。为了研究FKBP52在体内的作用，我们产生了 FKBP52基因缺陷小鼠。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最初形态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，这一提议将检验这一假设 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起关键作用 发展。我们将通过以下方式检验这一假说：1)我们将确定发展的 腹侧尿路上皮关闭与男性生殖器发育的机制；2)我们将确定 FKBP52在细胞和分子水平的雄激素受体信号中的作用；3)我们将研究 FKBP51到AR功能和利用小鼠遗传工具发育的尿道下裂。

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.