Decidualization, which involves the differentiation of the uterine stomal fibroblasts to decidual cells, is a major change that occurs in the primate endometrium after conception and is critical for the establishment and maintainance of pregnancy. The events leading to this cellular change at the biochemical and molecular level have yet to be fully explored. In vivo studies demonstrated that conceptus is essential to regulate this process in the primate. Based on our studies in baboon and human stromal fibroblasts the cytokine interleukin-1 (1L-1) was established as one of the possible mediators of decidualization.
In specific aim 1 we propose to study novel non-genomic signal transduction pathways induced by progesterone and determine whether progesterone interacts with IL-1 induced signal to regulate mitogen activated protein kinases. We propose that these pathways are critical during the initiation of decidualization in human and baboon stromal fibroblasts. The changes induced by progesterone in synergy with an embryonic signal lead to cytoskeletal reorganization and cell transformation.
In specific aim 2 we propose to investigate whether manipulation of the mechanical characteristics of cytoskeleton leading to its stabilization will prevent the decidualization process. We hypothesize that as result of cytoskeletal reorganization, cells exit their cell cycle, which allows them to differentiate. A cell cycle kinase important for the exit from the cell cycle, cyclin dependent kinase 4 (cdk4), is downregulated during in vivo and in vitro decidualization. Therefore, in specific aim 3 we will examine the possible mechanisms leading to cdk4 regulation and determine how manipulation of cdk4 expression will affect decidualization. It is our hope that the knowledge gained from our studies in the non-human primate and human stromal cells could contribute to therapies for diseases connected with decidualization defects. These may include endometrial dysfunction associated with infertility, pregnancy failures in patients with luteal phase defects, habitual abortions and/or insufficient placental development.
