Does type 1 diabetes change the microRNA expression profile on the uterus of ovariectomized mice submitted or not to estrogen replacement?

Abstract

Our group has established a mouse model of type 1 diabetes to investigate the impact of this disease on reproduction, particularly on the uterine environment (Favaro et al., 2010, 2013, 2104; FAPESP Grants: 07/55277-6 and Doctoral Fellowship: 04/14442-6). Through this model we showed that diabetes impairs endometrial decidualization and remodeling of the decidual extracellular matrix (ECM) (Favaro et al., 2013) as well as the structure, cell proliferation and ECM of the pregnant myometrium (Favaro et al., 2010; 2014). Bearing in mind that both uterine cell proliferation and ECM remodeling are regulated by estrogen and progesterone (Ramathal et al., 2009; Salgado et al., 2009, 2011, 2013; FAPESP Grants: 10/52543-0), we hypothesized that impairments on these processes by diabetes may be due to alterations on hormonal signaling in uterus. To investigate this question, we submitted alloxan-induced type 1 diabetic females to ovariectomy followed or not by estrogen treatment. (FAPESP Postdoctoral Fellowship: 11/22429-3). Estrogen and progesterone have been shown to regulate miRNA expression in the reproductive and non-reproductive organs. In the uterus of OVX mice, estrogen treatment modulates the proteins responsible for miRNA processing and maturation (Nothnick et al., 2010) as well as specific subsets of miRNAs (Nothnick and Healy, 2010). Estrogen treatment increased mirn155, mirn429 and mirn451 and reduced mirn181b and mirn204, miRNAs that may contribute to regulate genes associated to cell proliferation and ECM remodeling (Nothnick and Healy, 2010). The proliferative actions of estrogen are mediated by its action upon the expression of transcription factors, growth factors, cell cycle machinery components and miRNAs. MiRNAs are intimately related to cell proliferation control by targeting several mRNAs of cell cycle-associated molecules. For instance, miR-206 (Elliman et al., 2014), miR-365 (Kim et al., 2014), and many others have the capability to target cyclin D1 mRNA. Similarly, p27 transcript is regulated by the interaction with miR-221 and miR-222 (le Sage et al. 2007).Considering the major biological roles played by miRNAs in cellular behavior, we hypothesized these molecules may play a role in the alterations promoted by diabetes in the uterine environment. In this context, the goal of this research proposal is to investigate whether type 1 diabetes impacts on the miRNA expression profile in the uterus of ovarectomized mice submitted or not to estrogen treatment. Bioinformatical analysis of this data will indicate the targets of the miRNAs potentially altered by diabetes. The screening of miRNAs will provide informative data that may contribute to clarify the association between diabetes reproductive disorders. (AU)