Decidualization, which involves the differentiation of stromal fibroblasts into decidual cells, is critical for the establishment and maintenance of pregnancy. It is a major change that occurs in the primate endometrium after conception. Although the process has been the topic of intensive research for years, the events leading to the functional and morphological changes at the biochemical and molecular levels have yet to be explained. Based on our in vitro and in vivo results, possible embryonic origin cytokine interleukin-12 (IL-12) is one of the mediators of the decidualization process. Transcriptional coactivator with PDZ binding motif (TAZ) is a newly discovered transcriptional regulator that is suggested to control the switch between cell proliferation and differentiation. Based on our preliminary results, we hypothesize that TAZ is involved in the regulation of decidual gene expression, and thus contributes to decidualization induced by IL-12 in the presence of the steroid hormones (H): estrogen (E) and progesterone (P).
In specific aim 1, we propose to investigate the effect of manipulation of TAZ levels on decidualization of human stromal fibroblast cells and also to study the role of TAZ as a corepressor in the regulation of decidual gene expression. Decidualization induced in vitro by the IL-12 or the widely established exogenous stimulus cAMP (both in the presence of H) is accompanied by extensive changes in the cytoskeletal architecture. Cytoskeletal dynamics, rather than the absolute level of cytoskeletal stiffness or the precise organization of the cytoskeleton, are the more important elements of decidualization. We suggest that the cofilin (an actin binding protein)-dependent rearrangements of the cytoskeleton, followed by the translocation of cofilin into the nucleus, are key features of human stromal fibroblast cell decidualization. Our main goal in specific aim 2 will be to study the effect of manipulation of cytoskeletal dynamics, particularly modification of actin and cofilin properties, on the decidualization process. Defects in decidualization were described in endometriosis and infertility patients and we hypothesize that the ability of stromal cells to re-organize the cytoskeleton is compromised in these patients.
Specific aim 3 will be devoted to understanding of the differences in response to embryonic stimulus during decidualization between normal healthy stromal cells and diseased stromal cells (isolated from patients with endometriosis and from a baboon model of induced endometriosis). It is our hope that knowledge gained from our studies in human stromal cells and in the non human primate could contribute to therapies for diseases connected with decidualization defects, particularly endometriosis.
Infertility and endometriosis affect about 10% of women of reproductive age, and defects in the differentiation of stromal cells into decidual cells (decidualization) have been described in these patients. Studies proposed in this application will contribute to better understanding of the molecular mechanisms associated with these serious health issues, particularly by providing a new view on the involvement of the cytoskeleton in regulation of decidualization. Thus, in the long term our studies might provide new targets of intervention leading to improvements in diagnosis and treatment.
