Estrogen regulation of uterine microRNAs: Novel factors in MMP-9 regulation

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DESCRIPTION (provided by applicant): Matrix metalloproteinase-9 (MMP-9) is proposed to play an important role within the uterus from the time of post-natal uterine development through the period of establishment of pregnancy and subsequent parturition. Further, over-expression of MMP-9 or an imbalance in the MMP-9 to tissue inhibitor (TIMP) ratio has been associated with uterine pathologies such as dysfunctional uterine bleeding, endometriosis, infertility and endometrial carcinoma. Despite the proposed importance of this MMP in normal uterine physiology and uterine diseases, the steroidal regulation of MMP-9 is not clearly understood. Preliminary data in the current application suggest yet another layer of complexity in the regulation of this MMP. We present compelling evidence that MMP-9 transcript expression is decreased in response to early estrogen treatment, but protein and MMP-9 activity significantly increase. These observations suggest a novel and complex mechanism for estrogenic induction of uterine MMP-9 which, to the best of our knowledge, does exist in other organ or cell systems. As such, the objective of this proposal is to explore the mechanisms which impart this unique regulatory system within the uterus. We hypothesize that estrogen regulates uterine MMP-9 translation via a mechanism which includes microRNAs (miRNAs). To test this hypothesis, we propose two Specific Aims which will 1) characterize uterine miRNA expression in response to estrogen treatment, and 2) functionally demonstrate that those identified miRNA regulate MMP-9 translation within the uterus. In doing so, new light will be shed upon the estrogenic regulation of this important uterine MMP as well as the potential role of the uterine miRNA system in response to estrogen treatment. Collectively, the findings from the proposed studies will expand our knowledge on regulatory mechanisms for MMP-9 expression and provide the pioneering documentation of the uterine miRNA profile. These results will lead to further exploration of this system within the uterus and provide a better understanding on how uterine MMPs may be regulated and what functions miRNAs may play in this vital female organ. Summary: Controlled expression of matrix metalloproteinase-9 (MMP-9) is vital for normal uterine physiology while abnormal expression of MMP-9 is associated with uterine disease. Despite the importance of MMP-9 within the uterus, its regulation is poorly understood. The proposed studies will examine the complex regulation of MMP-9 within the uterus and decipher the novel role of microRNAs in the regulation of this protease. Enhancing our understanding on the regulation of MMP-9 expression may lead to the establishment of novel approaches to counteract mis-expression of this protease and the diseases associated with it.