The single most effective predictor of preterm birth is the state of cervix upon presentation with symptoms of preterm labor. The mechanisms underlying physiological cervical ripening at term are largely unknown, and the causes of preterm cervical dilation are even more elusive. Our laboratory, together with complementary expertise from other projects in this application, has expanded its long-term strength in the biology and physiology of human parturition to include a more integrated approach to delve deeply into the molecular transcriptional and genomic mechanisms that underpin the physiology of normal labor at term and the pathophysiology of preterm birth. Here, we propose (i) to determine if ER antagonists block preterm cervical ripening and labor, (ii) to explore the global effects of PR- and ER-mediated signaling pathways in human cervical cells and the cellular mechanisms by which PRs inhibit ER-mediated signaling, and (iii) to determine the role of ER-mediated signaling pathways in cervical ripening and dilation in vivo.

Public Health Relevance

PROJECT 3 NARRATIVE Preterm birth is the leading cause of infant mortality throughout the world. The overarching goal of this research is to enhance our understanding of the genes and regulatory mechanisms that mediate preterm cervical shortening during pregnancy and labor, a major cause of preterm birth. In the proposed research, we will use highly differentiated human cervical stromal cells and tissues and the pregnant guinea pig model to address the central roles of progesterone receptor (PR) and estrogen receptors (ER? and ER?) in maintenance of cervical competency and initiation of preterm cervical ripening, labor, and preterm birth. Next generation sequencing of RNA (RNA-seq), GRO-seq, combined with chromatin immunoprecipitation-deep sequencing (ChIP-seq) will be used to identify novel cervical genes and pathways that mediate premature cervical shortening and labor.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD087150-03
Application #
9604276
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Mahendroo, Mala (2018) Cervical hyaluronan biology in pregnancy, parturition and preterm birth. Matrix Biol :
Mogami, Haruta; Kishore, Annavarapu Hari; Word, R Ann (2018) Collagen Type 1 Accelerates Healing of Ruptured Fetal Membranes. Sci Rep 8:696
Itoh, Hiroko; Mogami, Haruta; Bou Nemer, Laurice et al. (2018) Endometrial stromal cell attachment and matrix homeostasis in abdominal wall endometriomas. Hum Reprod 33:280-291
Willcockson, Alexandra R; Nandu, Tulip; Liu, Cheuk-Lun et al. (2018) Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth. Biol Reprod 98:408-421
Manders, Dustin B; Kishore, Hari Annavarapu; Gazdar, Adi F et al. (2018) Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer. Oncotarget 9:14251-14267
Babayev, Samir N; Kanchwala, Mohammed; Xing, Chao et al. (2018) Thrombin Alters Human Endometrial Stromal Cell Differentiation During Decidualization. Reprod Sci :1933719118768705
Mogami, Haruta; Hari Kishore, Annavarapu; Akgul, Yucel et al. (2017) Healing of Preterm Ruptured Fetal Membranes. Sci Rep 7:13139
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
Kishore, Annavarapu Hari; Liang, Hanquan; Kanchwala, Mohammed et al. (2017) Prostaglandin dehydrogenase is a target for successful induction of cervical ripening. Proc Natl Acad Sci U S A 114:E6427-E6436
Babayev, Samir N; Park, Chan Woo; Keller, Patrick W et al. (2017) Androgens Upregulate Endometrial Epithelial Progesterone Receptor Expression: Potential Implications for Endometriosis. Reprod Sci 24:1454-1461

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