Estrogen synthesis is catalyzed by aromatase P450 (product of hCYP19 gene), which is expressed at very high levels in human placenta. hCYP19 gene expression is markedly induced during differentiation of human placental cells in culture;trophoblast differentiation and induction of hCYP19 expression are blocked by hypoxia. We recently observed that estrogen-related receptor 3 (ERR3) is O2-regulated and plays a crucial role together with estrogen receptor 1 (ER1) in the induction of hCYP19 expression during human trophoblast differentiation. Notably, ERR3 regulates K+ homeostasis in heart, stomach and kidney of mice via control of a number of hypertension-associated genes;further, ERR3 single nucleotide polymorphisms are correlated with altered blood pressure in humans. Based on the potential importance of placentally-derived estrogens in vascular adaptations during pregnancy and dysregulation of vascular remodeling in preeclampsia, a major goal of our research is to further define genetic and epigenetic mechanisms in O2-dependent regulation of hCYP19 gene expression during human trophoblast differentiation. In light of the suggested role of placental hypoxia in the pathogenesis of preeclampsia, we will identify ERR3 target genes that control Na+/K+ homeostasis and vascular tone in human and mouse placenta.
In Specific Aim 1, cultured human trophoblasts will be used to investigate genetic and epigenetic mechanisms whereby critical transcription factors and coregulators upregulate hCYP19 expression during human trophoblast differentiation and block its expression with hypoxia.
In Specific Aim 2, we will test the hypothesis that O2-dependent human trophoblast differentiation and induction of hCYP19 expression are mediated, in part, by specific microRNAs (miRNAs/miRs) that regulate expression of key transcription factors and coregulators.
In Specific Aim 3 we will investigate roles of ERR3 and of ER1 in O2-mediated regulation of placental genes that modulate K+ and blood pressure homeostasis and analyze their expression in placentas from preeclamptic vs. normal pregnancies and from wild-type and ERR3 null mice. We anticipate that our studies will shed new light on the etiology of this devastating disease.

Public Health Relevance

In humans, estrogens are synthesized in a variety of tissues, including the placenta, gonads, brain, bone and adipose. Estrogen production is catalyzed by the key enzyme, aromatase, encoded by the hCYP19 gene. In our proposed research, we will focus on defining the regulatory mechanisms that mediate aromatase expression in placenta and its regulation by O2 tension. In consideration of the suggested role of placental hypoxia in the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, we will investigate mechanisms for O2 regulation of genes that control Na+/K+ homeostasis and vascular tone in human and mouse placenta. We anticipate that our studies will shed new light on the etiology of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031206-29
Application #
8448225
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Margolis, Ronald N
Project Start
1983-08-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
29
Fiscal Year
2013
Total Cost
$387,057
Indirect Cost
$143,625
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Luo, Yanmin; Kumar, Premlata; Chen, Chien-Cheng et al. (2014) Estrogen-related receptor ? serves a role in blood pressure homeostasis during pregnancy. Mol Endocrinol 28:965-75
Mendelson, Carole R (2013) GRTH: a key to understanding androgen-mediated germ cell signaling. Endocrinology 154:1967-9
Luo, Yanmin; Kumar, Premlata; Mendelson, Carole R (2013) Estrogen-related receptor ? (ERR?) regulates oxygen-dependent expression of voltage-gated potassium (K+) channels and tissue kallikrein during human trophoblast differentiation. Mol Endocrinol 27:940-52
Kumar, Premlata; Luo, Yanmin; Tudela, Carmen et al. (2013) The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. Mol Cell Biol 33:1782-96
Chen, Chien-Cheng; Hardy, Daniel B; Mendelson, Carole R (2011) Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1 (MKP-1/DUSP1). J Biol Chem 286:43091-102
Kumar, Premlata; Mendelson, Carole R (2011) Estrogen-related receptor gamma (ERRgamma) mediates oxygen-dependent induction of aromatase (CYP19) gene expression during human trophoblast differentiation. Mol Endocrinol 25:1513-26
Kumar, Premlata; Kamat, Amrita; Mendelson, Carole R (2009) Estrogen receptor alpha (ERalpha) mediates stimulatory effects of estrogen on aromatase (CYP19) gene expression in human placenta. Mol Endocrinol 23:784-93
Bukulmez, Orhan; Hardy, Daniel B; Carr, Bruce R et al. (2008) Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: potential relevance to the pathogenesis of endometriosis. J Clin Endocrinol Metab 93:3471-7
Hardy, Daniel B; Janowski, Bethany A; Chen, Chien-Cheng et al. (2008) Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms. Mol Endocrinol 22:1812-24
Bukulmez, Orhan; Hardy, Daniel B; Carr, Bruce R et al. (2008) Inflammatory status influences aromatase and steroid receptor expression in endometriosis. Endocrinology 149:1190-204

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