In the previous study [
1], transcriptome profiling of granulosa cells from small (< 5 mm) and large (> 10 mm) follicles using high-throughput data sets were analyzed and “Integrated miRNA–mRNA Bipartite Network” was reconstructed. According to the next analysis, the most important signaling pathways involved in folliculogenesis were detected. These pathways were included Ras/ERK/MYC, PI3K/AKT/mTORC1 and ovarian steroidogenesis. Based on these findings, Ras/ERK/MYC and PI3K/AKT/mTORC1 pathways represent regulatory networks and fundamental signaling transduction for the majority of cellular physiological processes in folliculogenesis, such as growth, differentiation, migration, adhesion, proliferation, survival and protein synthesis. These pathways are mostly activated by alterations in ANGPT1, TEK, MYC, MAPK1, PIK3R1, MCL1 and EIF4EBP1 genes [
1]. Activation of such pathways is responsible of uncontrolled cellular physiological processes and can contribute to drug discovery. Combination therapies with pharmacological inhibitors or activators of these follicles pathways may have potential uses for the control of folliculogenesis process. Comparison of between dominant and subordinate follicles is a good model to investigate the activation of Ras/ERK/MYC and the PI3K/AKT/mTORC1 pathways as it is frequently affected by miRNAs that causes the activation or inhibition of pathways [
1]. Folliculogenesis is thought to occur by sequential accumulation of molecular alterations and genetic [
2]. Although, the mechanisms underlying follicle development are still unknown, several genes and metabolic pathways have been shown to carry molecular alterations in folliculogenesis. Folliculogenesis exhibit mutations in the Ras/RAF/mitogen activated protein kinase (MAPK) pathway. This mutation is known to play a key role in cell growth and proliferation of follicles, through activation of the ERK pathway [
1]. In particular, it occurs within the activation segment of the kinase domain and it results in an increased activity of the kinase itself. Constitutive activation of the kinase activity leads to unresponsitivity of negative feedback mechanisms within the ERK pathway [
3]. Previous studies show that ERK and AKT pathways are activated in parallel and the evidence that PI3K/AKT and MAPK/ERK1/2 cascades are interconnected is described [
4‐
6]. According to these findings, ERK and AKT pathways could represent targets for an otherwise devastating trait. Computational or dynamical modeling and Computer simulations are useful to analyze and to increase understanding of metabolic pathways [
7], specially involved in folliculogenesis and their complex interactions. On the other hand, MYC activity must be controlled in response to different environmental cues. Previous studies have showed that MYC is regulated at multiple levels, including post-transcriptional regulation [
8,
9] and autoregulation of MYC transcription [
10]. More recent discoveries indicate that MYC is also regulated at the protein level by the Ras effector pathways [
11‐
14]. The control of MYC dynamics by successive phosphorylation allows MYC to merge upstream signals from ERK and PI3K, which play key roles in controlling diverse cell fates [
15,
16]. As well as, major advances in understanding cell survival and translation control have come from the discovery of the intimate relationship between growth factor, the mitogen and hormone-responsive phosphatidylinositol 3-kinase (PI3K) pathway and the energy-sensing target of rapamycin (TOR) pathway. The PI3K and TOR pathways converge on common downstream targets: the ribosomal S6 kinases (S6Ks) and the translation initiation factor 4E-binding proteins (4E-BPs). Since the discovery that the TOR inhibitor rapamycin is effective in treatment of cell caused by misregulation of players in the PI3K pathway, the importance of the interplay between these two pathways is gaining greater recognition [
17]. In this work we survey here recent advances in our understanding of how the PI3K pathway impinges on the PI3K/AKT/mTORC1 pathway, how levels of expression in the PI3KR1 and EIF4EBP1pathways affect cell survival and translation control, and how the downstream targets of mTORC1 regulate cell survival. We develop a dynamic model that simulates both Ras/ERK/MYC and PI3K/AKT/mTORC1 pathways and their interactions for analyzing the reactions responsible for follicle development. Moreover, we modeled the behavior of the follicles in the presence of miRNAs expression, under the different stages of folliculogenesis.
There are several modeling approaches and their applications in current different research. These popular modeling approaches can simulate the dynamic changes of regulatory networks (metabolic pathways and signaling pathways), cell growth, and its environments, such as ordinary differential equations (ODEs), Petri nets, Boolean network, agent-based model, the system biology modeling approach considering genetic variation, and linear programming (LP) based model [
18]. Of these, because of modeling base on ODEs is able to predict precisely and continuously manner of each node in the network during the time, so in our work, it was considered. Overall, this model may be used for an in silico lab to study the effects of potential activators or inhibitors that may improve the response to standard treatments.