Preterm birth, the major cause of neonatal morbidity and mortality in the U.S., has increased steadily over the past two decades and now approaches ~13% of all live births. This alarming trend is due, in part, to our incomplete understanding of the pathways that maintain cervical integrity and uterine quiescence throughout pregnancy as well as those that promote cervical ripening and increased uterine contractility leading to labor. There is increasing evidence that both term and preterm labor are associated with an inflammatory response and that this is prevented throughout most of pregnancy by the anti-inflammatory actions of progesterone (P4) acting through it nuclear receptor (PR). The central theme of this proposal remains the elucidation of the molecular and cellular mechanisms that lead to the initiation of parturition, both at term and preterm. This theme is based on the overall hypothesis that the initiation of spontaneous labor in humans and in other mammals, is caused by a concerted series of biochemical and molecular events that culminate in an upregulation of inflammatory response pathways and a decrease in PR function. Although, preterm labor may have numerous causes, we propose that the signaling pathways that promote premature increase in uterine contractility, cervical ripening and expulsion of the fetus are similar to those at term. Thus, understanding the mechanisms leading to parturition at term should provide important insight into the development of therapeutic strategies to block these signaling mechanisms and prevent preterm labor. To achieve these goals, four interrelated projects and two cores are proposed. The goals of these Projects are: (1) To further define the genetic and epigenetic mechanisms whereby P4/PR inhibits myometrial contractility during pregnancy and by which inflammatory signaling upregulates contractile genes and represses PR function leading to labor, (2) to enhance our understanding of the role of hyaluronan (HA) in cervical ripening through elucidation of the effects of cervix-specific gene targeting of the key regulatory enzyme, hyaluronan synthase 2, and altered expression of HA degradative enzymes, hyaluronidases, (3) to elucidate the regulation of cervical ripening and dilation through a transcriptional network involving PRs, ERs, and the novel cervical transcription factor MiTF-CX, and (4) to test the hypothesis that physiological and pathological inflammatory responses in the uterus and cervix during pregnancy and parturition share a common set of molecular events that play crucial roles in the physiology of preterm and term parturition. We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth.

Public Health Relevance

: Premature births are the major cause of neonatal morbidity and mortality in the developed world. Identification of mechanisms that initiate parturition should lead to new insights into the pathophysiology of preterm birth and strategies to prevent it and its devastating consequences.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD011149-34
Application #
8610808
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (MC))
Program Officer
Ilekis, John V
Project Start
1997-04-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
34
Fiscal Year
2014
Total Cost
$1,248,534
Indirect Cost
$444,884
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
Lindqvist, Annika; Manders, Dustin; Word, R Ann (2013) The impact of reference gene selection in quantification of gene expression levels in guinea pig cervical tissues and cells. BMC Res Notes 6:34
Mogami, Haruta; Kishore, Annavarapu Hari; Shi, Haolin et al. (2013) Fetal fibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice. J Biol Chem 288:1953-66
Rosenfeld, Charles R; DeSpain, Kevin; Word, R Ann et al. (2012) Differential sensitivity to angiotensin II and norepinephrine in human uterine arteries. J Clin Endocrinol Metab 97:138-47
Rosa, Renata Giardini; Akgul, Yucel; Joazeiro, Paulo Pinto et al. (2012) Changes of large molecular weight hyaluronan and versican in the mouse pubic symphysis through pregnancy. Biol Reprod 86:44
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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