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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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University of Texas Sw Medical Center Dallas
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Akgul, Yucel; Word, R Ann; Ensign, Laura M et al. (2014) Hyaluronan in cervical epithelia protects against infection-mediated preterm birth. J Clin Invest 124:5481-9
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
Kishore, A Hari; Owens, David; Word, R Ann (2014) Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor-mediated cervical cell-specific mechanisms. J Clin Endocrinol Metab 99:1006-18
Montalbano, Alina P; Hawgood, Samuel; Mendelson, Carole R (2013) Mice deficient in surfactant protein A (SP-A) and SP-D or in TLR2 manifest delayed parturition and decreased expression of inflammatory and contractile genes. Endocrinology 154:483-98
Mendelson, Carole R (2013) GRTH: a key to understanding androgen-mediated germ cell signaling. Endocrinology 154:1967-9
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Itoh, Hiroko; Kishore, Annavarapu Hari; Lindqvist, Annika et al. (2012) Transforming growth factor ýý1 (TGFýý1) and progesterone regulate matrix metalloproteinases (MMP) in human endometrial stromal cells. J Clin Endocrinol Metab 97:E888-97

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