Successful parturition in all mammalian species requires a timely onset of uterine contractions and remodeling of the cervix to allow passage of the fetus through the birth canal. The molecular mechanisms controlling these intertwined processes remain poorly understood. Each year, some 4.5 million severely premature infants are born worldwide due to failure of normal parturition, and complications associated with delivery in post term pregnancies cause innumerable problems in both mother and child. The proposed studies are designed to further our understanding of the molecular processes that facilitate cervical softening and ripening. Studies in normal mice and mice with defects in cervical ripening have revealed an important role of the enzyme hyaluronan synthase 2 in production of the glycosaminoglycan hyaluronan (HA). We hypothesize HA has multiple roles in the ripening process. The first role is a structural one in which HA provides a hydrated loosely associated matdx to allow appropriate restructuring of the matrix. A second role of HA we propose, is in initiation of cell signaling events required for a normal inflammatory response during the ripening process. In vivo and in vitro studies will be carried out to understand regulation of hyaluronan synthase 2 in cervical ripening. Studies designed to evaluate the physiological functions of HA will be initiated. This includes identification of HA-binding proteins in the cervix that are critical to HA function, evaluation of changes in HA molecular weight and characterization of the HA cell surface receptor, CD44. Finally, we will determine if abnormally elevated or reduced HA content plays a role in complications associated with cervical incompetence, threatened preterm labor, or in women with postterm pregnancies who fail to progress after induction of labor. The integrated approaches applied in these studies in combination with the other projects in this proposal will provide novel molecular insight into the mechanisms controlling parturition in mice and women and will establish a framework from which to devise therapies to prevent complications associated with parturition.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD011149-30
Application #
7750554
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
30
Fiscal Year
2009
Total Cost
$285,959
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 :
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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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