The research proposed is designed to characterize the functional phenotypes of the uterus during pregnancy (before and during labor) and to define the cellular changes that establish the phenotypic differences. The studies described are closely aligned with those designed to determine the biomolecular mechanisms by which the transitions in parturition phase are effected. The studies are based on the hypothesis that thre are three major components of a fail-safe system that ensures myometrial quiescence for the first 90-95 percent of human pregnancy: (i) the actions of estrogen-progesterone; (ii) hormones, neuropeptides and eicosanoids acting via heptahelical receptors linked to Galpha/S adenylyl cyclase; and, (iii) natriuretic peptide-activated membrane receptor/guanylyl cyclase, which effects an increase in intracellular cGMP. The 3 system components that serve to effect myometrial quiescence must be muted late in pregnancy as uterine phase O is suspended. There also is a group of ligands that act in myometrium via heptahelical receptors linked to Galpha/i/q/11-causing inhibition of adenylyl cyclase and activation of phospholipase C (PLC). An increase in responsiveness to Galpha/i/q/11-linked receptor ligands likely facilitates the establishment of uterine phase 1, ultimately eventuating in the completion of the uterine transition to phase 2, i.e., active labor. Myometrial membrane preparations from pre-term and term pregnancies (before and during labor) will be used to evaluate responsiveness to multiple (9 different) ligands operative via Galpha/S- linked heptahelical receptors that activate adenylyl cyclase. The cAMP- activation state of the myometrium will be evaluated by determining endogenous levels of cAMP and the steady-state activity of protein kinase A (PKA). Various components of the system will be explored to define the nature of cellular changes that account for phenotypic differences among tissues: heptahelical receptors and linkage to G-proteins, total (activatable) adenylyl cyclase, G-protein expression and subcellular distribution. Responsiveness of myometrial membrane preparation to activation of membrane receptor/guanylyl cyclase by natriuretic peptides will be evaluated together with the levels of endogenous cGMP and the steady state cGMP-induced protein kinase. Tissue responsiveness to ligands that act via Galpha/i/q/11,-linked heptahelical receptors to activate phospholipase C also will be assessed. Estrogen receptor-transfected human myometrial cells will be used to define the cause of cellular changes that account for the changes in functional phenotypes.
| Mahendroo, Mala (2018) Cervical hyaluronan biology in pregnancy, parturition and preterm birth. Matrix Biol : |
| 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 |
| Chen, Chien-Cheng; Montalbano, Alina P; Hussain, Imran et al. (2017) The transcriptional repressor GATAD2B mediates progesterone receptor suppression of myometrial contractile gene expression. J Biol Chem 292:12560-12576 |
| Chigusa, Yoshitsugu; Kishore, Annavarapu Hari; Mogami, Haruta et al. (2016) Nrf2 Activation Inhibits Effects of Thrombin in Human Amnion Cells and Thrombin-Induced Preterm Birth in Mice. J Clin Endocrinol Metab 101:2612-21 |
| Gao, Lu; Wang, Gang; Liu, Wei-Na et al. (2016) Reciprocal Feedback Between miR-181a and E2/ER? in Myometrium Enhances Inflammation Leading to Labor. J Clin Endocrinol Metab 101:3646-3656 |
| Jimenez, Patricia T; Mainigi, Monica A; Word, R Ann et al. (2016) miR-200 Regulates Endometrial Development During Early Pregnancy. Mol Endocrinol 30:977-87 |
| Eskiocak, Ugur; Ramesh, Vijayashree; Gill, Jennifer G et al. (2016) Synergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma. Nat Commun 7:12336 |
| Gao, Lu; Rabbitt, Elizabeth H; Condon, Jennifer C et al. (2015) Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J Clin Invest 125:2808-24 |
| Renthal, Nora E; Williams, Koriand'r C; Montalbano, Alina P et al. (2015) Molecular Regulation of Parturition: A Myometrial Perspective. Cold Spring Harb Perspect Med 5: |
| 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 |
Showing the most recent 10 out of 55 publications
