Dissecting the functional role of miRNAs in decidualization

剖析 miRNA 在蜕膜化中的功能作用

• 批准号: 8516680
• 负责人: Warren B Nothnick
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516680
• 关键词: 3' Untranslated Regions; Applications Grants; Binding; Biological Assay; Biological Process; Cells; Clinical; Couples; Data; Decidual Cell Reactions; Disease; Emotional; Endometrial Stromal Cell; Endometrium; Event; Functional disorder; Future; HOXA10 gene; Human; In Situ Hybridization; In Vitro; Infertility; Lead; Light; Mediator of activation protein; Messenger RNA; MicroRNAs; Mus; Outcome; Pathway interactions; Phenotype; Play; Pregnancy; Pregnancy loss; Process; Recurrence; Reporter; Repression; Research; Role; Small Interfering RNA; Stromal Cells; Testing; Time; Transcript; Translating; Translations; Western Blotting; Woman; base; cDNA Arrays; combinatorial; failure Implantation; in vitro Model; in vivo; innovation; insight; mouse model; natural Blastocyst Implantation; novel; protein expression; public health relevance

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.

描述（由申请人提供）：复发性流产 (RPL) 对不孕不育的夫妇具有重大的情感和经济影响。 RPL 被认为会产生 子宫内膜基质细胞无法表达适当的蜕膜表型（Teklenburg 等人，2010 年综述），但其原因尚不清楚。 MicroRNA (miRNA) 是一类调节转录后翻译的小调节 RNA。 miRNA 已被证明可以调节多种生物过程，并与妊娠的建立有关。最近，反复着床失败的女性子宫内膜中 miRNA 错误表达已被记录（Revel 等，2011）。除了这种描述以及与可能影响胚胎植入的推定因素的相关性之外，几乎没有任何功能数据或对 miRNA 调节蜕膜化机制的理解？ 这项探索性试点拨款申请的目的是检查 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方法（miRNA 的 RIP 测定）来识别在蜕膜化过程中受 miR-27b 功能调节的 mRNA。我们预计我们将识别（并确认）已知对蜕膜化至关重要的靶标（例如 HOXA10 和 FOXO1）以及新颖的、不可预见的靶标。然后，我们将使用特征良好的胚胎植入和蜕膜化小鼠模型来检查这些新靶点的表达，以获得对成功妊娠至关重要的介质和机制的新见解。这项研究的结果有可能为特定 miRNA 在蜕膜化过程中的作用提供新的见解。最终，这些新信息将用于增进我们对复发性流产的理解，并制定新策略来纠正这一临床难题。