Our laboratory recently identified a novel murine G-protein coupled receptor (GPCR) that becomes up- regulated (7-fold) in the decidualizing stromal compartment in response to the implanting embryo. RT-PCR and in situ hybridization reveal that the novel GPCR is temporally and spatially restricted in its expression pattern to the stromal compartment of the uterus during pregnancy and is not expressed in other tissues/organs. Studies using human decidualized stromal cells suggest that a functional counterpart is expressed during human decidualization. The proposed studies will therefore have likely implications for human pregnancy. Likewise, it was established that renin, an enzyme that generates active hemodynamic peptides through proteolytic cleavage of angiotensinogen, is up-regulated in the endometrium during early gestation. Our hypothesis is that the orphaned GPCR is functionally required for normal pregnancy, and that this novel receptor serves to mediate angiotensin-(1-7)-induced vasodilation at the maternal-embryo interface.
In Specific Aim 1 we propose to demonstrate the functional requirement of the receptor in insertional mutagenesis studies in which cre recombinase is inserted into the receptor gene locus. Particular focus will be given to uterine vascular dynamics and prostaglandin production during early pregnancy. One important aspect of generating the GPCR-cre mouse line is that, due to the restricted expression of the receptor to the decidualizing uterus, the mouse can be used in future experiments as a much needed research tool to study other genes thought to be important for uterine decidualization using Cre/LoxP technology.
In Specific Aim 2, we will test the functionality of the GPCR promoter to drive transgene expression. Findings derived from the successful completion of this research project will have broad application to the field of receptor signaling and will advance our understanding of maternal-embryo interactions.
An estimated 25-60% of conceptions result in pregnancy failure depending upon the mammalian species. In humans, recurrent pregnancy loss occurs in about 1% of pregnancies and, as such, is among the most common complications to pregnancy. Disruption of the renin- angiotensin system, particularly components that regulate vasodilation, is thought to be causally linked to the development of preeclampsia in human pregnancy. This project will establish a functional role for a novel GPCR that is hypothesized to mediate actions of the renin-angiotensin system. PUBLIC HEALTH RELEVANCE: Pregnancy failure during the early stages of gestation occurs in 25%-60% of conceptions depending upon the mammalian species. In humans, recurrent pregnancy loss, defined as having had two or more miscarriages, occurs in about 1% of women trying to conceive and is among the most common complications to pregnancy. The events by which the developing embryo modifies the uterine environment to suit its needs are poorly understood. In the proposal, we plan to study a previously uncharacterized receptor expressed in the uterus in response to the embryo during early gestation. We believe that the receptor plays a pivotal role in regulating early gestation by allowing adequate influx of maternal nutrient to support the developing embryo prior to development of its own placenta. As part of this application, we will develop new research tools that can be used to better understand the molecular events of early pregnancy and uterine physiology.
| Clark, N C; Pru, C A; Pru, J K (2017) Novel Regulators of Hemodynamics in the Pregnant Uterus. Prog Mol Biol Transl Sci 145:181-216 |
