Dissecting the functional role of miRNAs in decidualization

描述（由申请人提供）：复发性妊娠丢失（RPL）对面临不孕症的夫妇有显着的情感和经济影响。RPL被认为是导致 来自子宫内膜基质细胞不能表达适当的蜕膜表型（综述于Teklenburg等，2010年），但其原因尚不清楚。microRNA（miRNAs）是一类调节转录后翻译的小分子调控RNA。miRNAs已被证明可以调节多种生物学过程，并与妊娠的建立有关。最近，已经记录了来自患有反复着床失败的女性的子宫内膜中的miRNA错误表达（Revel et al.，2011年）。除了这种描述和与可能影响胚胎着床的假定因素的相关性之外，很少或没有功能数据，也没有对miRNAs调节蜕膜化的机制的理解，已经提出？ 这项探索性试点资助申请的目的是研究miRNA错误表达损害基质细胞蜕膜化的功能机制。在拟议的应用中，我们将应用一种创新的方法（RIP检测miRNAs）来识别在蜕膜化过程中受miR-27 b功能调控的mRNAs。我们预计，我们将确定（并确认）已知对蜕膜化至关重要的靶点（如HOXA 10和FOXO 1）以及新的、不可预见的靶点。然后，我们将研究这些新的目标的表达，使用一个良好的表征胚胎植入和蜕膜化的小鼠模型，获得新的见解的介质和机制，这是成功怀孕的关键。这项研究的结果有可能为特定miRNAs在蜕膜化过程中的作用提供新的见解。最终，这一新的信息将被应用于促进我们对复发性流产的理解，并制定新的策略来纠正这一临床难题。

DESCRIPTION (provided by applicant): Recurrent pregnancy loss (RPL) has significant emotional and financial impact on couples who are faced with infertility. RPL is believed to result from the inability of endometrial stromal cells to express an appropriate decidual phenotype (reviewed in Teklenburg et al., 2010), but the reasons for this are not clearly understood. MicroRNAs (miRNAs) are a class of small regulatory RNAs which modulate post-transcriptional translation. miRNAs have been shown to regulate a variety of biological processes and have been implicated in the establishment of pregnancy. Recently, miRNA mis-expression in endometrium from women who suffer from repeated implantation failure has been documented (Revel et al., 2011). Beyond this description and correlation with putative factors which may impact embryo implantation, little to no functional data nor an understanding on the mechanisms by which miRNAs regulate decidualization, have been presented? The objective of this exploratory pilot grant application is to examine the functional mechanisms by which miRNA mis-expression impairs stromal cell decidualization. In the proposed application, we will apply an innovative approach (RIP assay for miRNAs) to identify those mRNAs which are functionally regulated by miR- 27b during the process of decidualization. We anticipate that we will identify (and confirm) targets which are known to be essential for decidualization (such as HOXA10 and FOXO1) as well as novel, unforeseen targets. We will then examine the expression of these novel targets using a well-characterized mouse model of embryo implantation and decidualization gaining new insight into the mediators and mechanisms which are critical for successful pregnancy. The outcomes from this proposed research have the potential to provide novel insight into the role that specific miRNAs play in the process of decidualization. Ultimately this novel information will be applied to advance our understanding on recurrent pregnancy loss and develop new strategies towards correcting this clinical conundrum.