Dissecting the functional role of miRNAs in decidualization

描述(申请人提供)：复发性妊娠丢失(RPL)对面临不孕不育的夫妇有重大的情感和经济影响。RPL被认为会导致 从子宫内膜间质细胞不能表达适当的蜕膜表型(在特克伦堡等人，2010年回顾)，但其原因尚不清楚。MicroRNAs(MiRNAs)是一类调节转录后翻译的小分子调控RNA。MiRNAs已被证明调节多种生物学过程，并与妊娠的建立有关。最近，反复植入失败的妇女子宫内膜中miRNA的错误表达已被记录下来(Revel等人，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，很少或根本没有功能数据，也没有关于miRNAs调节蜕膜化的机制的了解？这项探索性的试点拨款申请的目的是研究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(miRNAs的RIP分析)来识别在蜕膜化过程中受miR-27b功能调节的mRNAs。我们预计，我们将确定(并确认)已知的对去中心化至关重要的目标(如HOXA10和FOXO1)以及新的、不可预见的目标。然后，我们将使用一个具有良好特性的胚胎植入和蜕膜形成的小鼠模型来研究这些新靶点的表达，从而获得对成功怀孕至关重要的介质和机制的新见解。这项拟议研究的结果有可能为特定miRNAs在蜕膜化过程中所起的作用提供新的见解。最终，这一新的信息将被用于促进我们对反复妊娠丢失的理解，并开发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.