MICRORNA REGULATION OF DEVELOPMENT AND FUNCTION OF THE FEMALE REPRODUCTIVE TRACT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 子宫是所有高等物种成功繁殖所必需的。 了解有助于子宫发育和功能的分子机制对于成功生殖至关重要。 Dicer是一种产生microRNA（miRNAs）并共同调节特定基因产物的转录后调节的酶。 最近，已经提出miRNAs在胚胎着床以及在人类子宫内膜和女性疾病子宫内膜异位症的病理生理学中发挥作用。 总的来说，这些研究表明，Dicer及其酶产物（即miRNA）在多器官系统的分子调节中发挥关键作用，包括生殖功能，特别是子宫着床和子宫病理生理条件。 在所提出的申请中待测试的总体假设是RNase III内切核酸酶Dicer通过加工miRNA在出生后子宫发育和功能中起重要作用。 为了验证这一假设，我们制定了两个具体的目标，这将：1）通过破坏Dicer表达来确定Dicer/miRNAs在出生后子宫发育和功能中的功能作用，以及2）鉴定影响出生后子宫发育和功能的特异性miRNAs。 为了实现这些目标，我们将利用突变小鼠，其中Dicer已经从雌性生殖道中有条件地删除。 主要结局指标将包括评估女性生殖道的外观和功能（Aim I），并鉴定导致预期发育/功能异常的miRNA和/或其蛋白质靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The uterus is necessary for successful propagation of all higher species. Understanding the molecular mechanisms that contribute to the development and function of the uterus is essential for successful reproduction. Dicer is an enzyme that generates microRNAs (miRNAs) and together regulatet post-transcriptional regulation of specific gene products. Recently, miRNAs have been proposed to play a role in embryo implantation as well as in the human endometrium and in the pathophysiology of the female disease endometriosis. Collectively, these studies suggest that Dicer and it's enzymatic products (i.e. miRNAs) play a pivotal role in the molecular regulation of multiple organ systems, including reproductive function and specifically uterine implantation and uterine pathophysiological conditions. The overall hypothesis to be tested in the proposed application is that the RNase III endonucleases, Dicer, through processing of miRNAs plays a vital role in post-natal uterine development and function. To test this hypothesis, we have formulated two specific aims which will: 1) determine the functional role of Dicer/miRNAs in post-natal uterine development and function by disrupting Dicer expression and 2) identify specific miRNAs that impact post-natal uterine development and function. To accomplish these goals we will utilize mutant mice in which Dicer has been conditionally deleted from the female reproductive tract. The main outcome measures will include assessment of the appearance and function of the female reproductive tract (Aim I) and identifying the miRNAs and/or their protein targets which lead to the anticipated developmental/functional abnormalities.