Myometrial PRs/ERs:targets for the prevention of preterm labor

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Premature birth occurs in 8-12% of pregnancies and causes 70-80% of neonatal mortality and morbidity. This major public health problem is exacerbated by our inability to stop preterm labor. Progress in addressing this issue has been slow mainly because we do not fully understand how the contractility of the human pregnancy uterus is controlled. Our research aims to fill this knowledge-gap by asking how the key hormonal regulators of labor, the steroid hormones progesterone and estrogen, affect myometrial contractility. In all mammals studied to date, progesterone prevents labor by suppressing myometrial contractility, whereas estrogens promote labor by transforming the myometrium to a highly contractile state. Consistent with these actions, labor is initiated by the withdrawal of progesterone and the concurrent increase in estrogenic influences on the myometrium. In human parturition, these events occur by decreased myometrial progesterone responsiveness (i.e., functional progesterone withdrawal) and increased myometrial estrogen responsiveness (i.e., functional estrogen activation) each mediated, in part, by specific changes, respectively, in myometrial progesterone and estrogen receptor (PR and ER) expression. Based on this paradigm, we propose that preterm labor could be prevented by treatments that increase myometrial progesterone responsiveness and/or inhibit estrogenic actions on the myometrium. Therefore, for Specific Aim 1 we will determine whether modulators of PR expression and estrogen responsiveness alter progesterone responsiveness and myometrial contractile capacity in human pregnancy myometrial cells. To facilitate progress in understanding the control of human parturition we need to improve existing experimental models of the human pregnancy myometrium and develop novel approaches to study how its contractility is controlled. To date the best in vitro model for the human pregnancy myometrium is the PHM1- 31 immortalized myometrial cell line, developed from a term (not in labor) myometrium. These cells have a stable smooth muscle cell phenotype and consistent with their origin from the pregnancy uterus, express many of the contraction associated genes typical of the human pregnancy myometrium. Therefore, for Specific Aim 2 we will use retroviral transduction to improve the PHM1-31 model. To this end we will produce stable genetically modified PHM1-31 sub-lines expressing functional transgenes. These sub-lines will be used to examine the process and control of myometrial progesterone and estrogen responsiveness. The development of specifically engineered and genetically stable PHM1-31 sub-lines will be an important experimental tool for research aimed at elucidating hormonal control of human birth so that we can develop therapeutic strategies to prevent preterm birth.