Preterm birth occurs in 12.5% of pregnancies, affects 500,000 children per year in the United States and has a financial toll that exceeds $26 billion per year. A greater understanding of the molecular processes that regulate parturition are essential for prevention of prematurity. Towards this end our research is aimed at understanding how the cervix remodels in preparation for birth. One unique aspect of cervical ripening and dilation at the end of pregnancy is the marked increase in expression of hyaluronan synthase 2 resulting in increased hyaluronan (HA) production. We propose that hyaluronan has multiple roles in the cervix that are dependent on the HA size, structure, binding partners and cell type. In the current study we will test the hypothesis that high molecular weight HA has important functions during ripening to increase tissue viscoelasticity and that the breakdown to low molecular weight HA serves two functions: 1) to allow loss of tissue integrity and maximal tissue compliance with onset of uterine contraction and 2) to modulate inflammatory events needed for postpartum tissue repair. These functions of HA in cervical remodeling will be tested in mice with a cervix specific depletion of Has2. Temporal changes in hyaluronidase activity will be measured in the mouse and guinea pig cervix during cervical ripening, in labor and postpartum and correlated with changes in biomechanical properties of the cervix as well as migration, activation and phenotype of inflammatory cells before, during and after birth. The interaction of HA with CD44 and toll like receptors and activation of downstream signaling pathways will be evaluated in both macrophage and cervical epithelial cell lines and compared to pathways induced by lipopolysacharide (LPS). The ability of HA to compete with LPS and reduce rates of infection-mediated PTB will be tested in wild type, CD44'''and TLR4''mice. Finally investigations will be carried out using cervical mucus from pregnant women to determine if increased hyaluronidase activity and low molecular weight HA correlates with progression of pregnancy and degree of cervical ripening as determined by a Bishops score. Taken together, these studies will enhance our understanding of the physiological process of cervical remodeling, provide insight into how a matrix molecule can modulate processes important in distinct phases of cervical remodeling before and after birth and will provide the basis for future studies aimed at development of therapies for prevention of complications associated with both preterm and postterm birth.

Public Health Relevance

Understanding the molecular processes that modulate term cervical remodeling is critical to identify causes of premature remodeling that result in pretemn birth. Hyaluronan (HA) has important proposed roles during multiple phases of remodeling before and after birth and in the current study these functions will be better defined. Therapeutic targets may be an outcome as our study will test the efficacy of HA treatment to reduce rates of infection mediated preterm birth and will provide insights as to whether hyaluronidase injection into the cervix mav have utilitv in oromotina cervical ripening post term oreanancv or at the time of labor. Project/Performance

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD011149-33
Application #
8442192
Study Section
Special Emphasis Panel (ZHD1-DSR-Z)
Project Start
Project End
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
33
Fiscal Year
2013
Total Cost
$262,477
Indirect Cost
$97,449
Name
University of Texas Sw Medical Center Dallas
Department
Type
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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