The overall goal of this proposal is to understand the mechanisms by which the cervix normally resists effacement, and dilation imposed by the gravitational effects of the fetus. Cervical shortening in the second trimester predicts preterm birth suggesting that cervical changes occur several weeks prior to uterine contractions of preterm labor. These findings, together with clinical evidence that cervical ripening precedes myometrial contractions of labor in both preterm and term parturition, indicate that to impact the preterm birth rate, we need to understand the biologic mechanisms that regulate progressive changes in cervical function during pregnancy. Our results obtained during the previous funding period suggest that cervical competency during pregnancy is an active process mediated by transcriptional networks within cervical stromal cells. One of the transcription factors involved in cervical competency is MiTF-CX. By way of preliminary studies, we found that MiTF-CX not only represses IL-8 and TGF-|3 signaling, but also increases and modulates progesterone receptor isoforms (PR-B and PR-A). Loss of MiTF-CX in cervical stromal cells in the dilated cervix in labor is associated with significant loss of both PR isoforms. Decreased progesterone responsiveness is thereby associated with increased expression of ER|3 and upregulation of estrogen-mediated signaling pathways in the cervix. The overall hvpothesis of this proposal is that cervical competency during pregnancy is maintained by a transcriptional program that opposes estrogen-mediated signaling and inflammatory response pathways. Further, we suggest that loss of these transcriptional events leads to increased chemokines, immune cell infiltration, protease activation, dissolution of the ECM, and cervical dilation. The goal of this renewal application is to extend our studies investigating the mechanisms by which key transcription factors (MiTF-CX, PRs, and ERs) interact to alter gene expression in human cervical stromal cells.
Our specific aims are (1) to determine the mechanisms by which MiTF-CX regulates PR and 15-hydroxyprostaglandin dehydrogenase {PGDH) in cervical stromal cells, (2) to explore the global effects of PR- and ER- mediated signaling pathways and the cellular mechanisms by which PRs inhibit ER-mediated signaling in cervical stromal cells, and (3) to determine the role of ERq-and ERP-mediated signaling pathways in cervical ripening and dilation in vivo. The studies will enhance our knowledge regarding direct estrogen- and progesterone-regulated signaling pathways and their physiological significance in the cervix in vitro and vivo.
Premature births are the major cause of neonatal morbidity and mortality in the developed world Identification of mechanisms that initiate parturition and cervical ripening should lead to new insights into the pathophysiology of preterm birth and strategies to prevent it and its devastating consequences.
| Mahendroo, Mala (2018) Cervical hyaluronan biology in pregnancy, parturition and preterm birth. Matrix Biol : |
| Mendelson, Carole R; Montalbano, Alina P; Gao, Lu (2017) Fetal-to-maternal signaling in the timing of birth. J Steroid Biochem Mol Biol 170:19-27 |
| Chen, Chien-Cheng; Montalbano, Alina P; Hussain, Imran et al. (2017) The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. J Biol Chem 292:12560-12576 |
| Chigusa, Yoshitsugu; Kishore, Annavarapu Hari; Mogami, Haruta et al. (2016) Nrf2 Activation Inhibits Effects of Thrombin in Human Amnion Cells and Thrombin-Induced Preterm Birth in Mice. J Clin Endocrinol Metab 101:2612-21 |
| Gao, Lu; Wang, Gang; Liu, Wei-Na et al. (2016) Reciprocal Feedback Between miR-181a and E2/ER? in Myometrium Enhances Inflammation Leading to Labor. J Clin Endocrinol Metab 101:3646-3656 |
| Jimenez, Patricia T; Mainigi, Monica A; Word, R Ann et al. (2016) miR-200 Regulates Endometrial Development During Early Pregnancy. Mol Endocrinol 30:977-87 |
| Eskiocak, Ugur; Ramesh, Vijayashree; Gill, Jennifer G et al. (2016) Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma. Nat Commun 7:12336 |
| Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C et al. (2015) Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J Clin Invest 125:2808-24 |
| Renthal, Nora E; Williams, Koriand'r C; Montalbano, Alina P et al. (2015) Molecular Regulation of Parturition: A Myometrial Perspective. Cold Spring Harb Perspect Med 5: |
| Mogami, Haruta; Keller, Patrick W; Shi, Haolin et al. (2014) Effect of thrombin on human amnion mesenchymal cells, mouse fetal membranes, and preterm birth. J Biol Chem 289:13295-307 |
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