Glycodelin Regulation in Polycystic Ovarian Syndrome

描述（由申请人提供）：人类胚胎植入是一个相对不可靠的过程，大约30%的受孕周期失败。与着床失败相关的一种常见病症是多囊卵巢综合征（PCOS），这是本申请的临床焦点。着床是一个复杂的高度调节的过程，依赖于子宫内膜容受性的精确内分泌和旁分泌协调。在子宫内膜表面上皮中已鉴定出几种具有不同功能的蛋白质。这些蛋白的表达与胚泡附着和滋养层侵入的时间相一致。卵巢激素，特别是孕酮，被认为是在狭窄的着床窗口中表达的子宫内膜蛋白的主要调节剂。先前的研究已经确定glycodelin-A（GdA）在分泌期和早期妊娠子宫内膜上皮中表达。GdA浓度在PCOS以及其他原因导致的着床失败和复发性妊娠丢失的病例中降低。我们发现，GdA的转录直接受孕激素受体复合物的调节，其生物活性之一是抑制单核细胞趋化性。本申请中提出的实验旨在评估导致PCOS中GdA产量降低的分子机制。实验室实验将在体外模型中建立雄激素、促黄体生成激素（LH）和胰岛素对GdA生物合成的作用。将评价单核细胞和其他潜在靶细胞中的GdA信号传导和作用。GdA受体将被纯化和表征。将对正常生育妇女和多囊卵巢综合征妇女进行病例对照研究，以剖析后一组中涉及GdA失调的潜在途径。将通过子宫内膜活检诱导和监测模拟周期，以确定升高的雄激素、LH和胰岛素与受损的GdA表达的相关性。最后，一个非侵入性的定量评价宫颈液GdA将开发作为一个潜在的标志物，一个“开放”的植入窗口。子宫内膜容受性最佳状态的表征将具有广泛的公共卫生意义。患有PCOS，不孕症，反复妊娠丢失，甚至后期妊娠并发症如先兆子痫和宫内生长受限的妇女将受益于更好地了解植入和胎盘的细胞生理学。

DESCRIPTION (provided by applicant): Human embryonic implantation is a relatively unreliable process, failing in approximately 30% of conception cycles. One common condition associated with implantation failure is polycystic ovary syndrome (PCOS), which is the clinical focus of this application. Implantation is a complex and highly regulated process dependent upon precise endocrine and paracrine coordination of endometrial receptivity. Several proteins with diverse functions have been identified in the endometrial surface epithelium. The expression of these proteins coincides with the timing of blastocyst attachment and trophoblast invasion. Ovarian hormones, and progesterone in particular, are believed to be the primary regulators of endometrial proteins expressed in the narrow window of implantation. Prior studies have established that glycodelin-A (GdA) is expressed in secretory phase and early pregnancy endometrial epithelium. GdA concentrations are decreased in cases with PCOS as well as in other causes of failed implantation and recurrent pregnancy loss. We discovered that GdA transcription is directly regulated by progestin-receptor complexes and that one of its biological activities is the inhibition of monocyte chemotaxis. Experiments proposed in this application are designed to evaluate the molecular mechanisms resulting in lower GdA production in PCOS. Laboratory experiments will establish the roles of androgens, luteinizing hormone (LH) and insulin on GdA biosynthesis in vitro models. GdA signaling and action in monocytes and other potential target cells will be evaluated. The GdA receptor will be purified and characterized. A case-control study of normal fertile women and women with PCOS will be conducted to dissect the potential pathways involved in GdA dysregulation in the latter group. Mock cycles will be induced and monitored by endometrial biopsies to determine the correlation of elevated androgens, LH and insulin to impaired GdA expression. Finally, a noninvasive quantitative evaluation of cervical fluid GdA will be developed as a potential marker for an "open" implantation window. Characterization of an optimal state for endometrial receptivity will have broad public health implications. Women suffering PCOS, infertility, recurrent pregnancy loss, and even later pregnancy complications such as preeclampsia and intrauterine growth restriction, will benefit from a better understanding of the cellular physiology of implantation and placentation.