Limited published reports and preliminary experiments conducted by the PI suggest that the rodent and primate ovary possess the capacity to produce and metabolize epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA). Preliminary experiments also suggest that EETs play a role in ovulation as an inhibitor of EET metabolism significantly increased the number of oocytes released in mice following injection of an ovulatory dose of gonadotropin. Therefore, studies are designed using rodents and primates to test the hypothesis that EETs are synthesized (Aim number 1), inactivated (Aim number 2), and directly affect molecular processes (Aim number 3) and oocyte release (Aim number 4) in the ovulatory follicle. Expression of EET generating cytochrome P450 (CYP) epoxygenases during the periovulatory interval and their cellular localization will be determined by real-time PCR and in situ hybridization, respectively. The specific EET isomer(s) produced during the periovulatory interval will be determined by gas chromatography/mass spectrometry. Recently, the PI has cloned a novel ovary-selective isoform of soluble (cytoplasmic) epoxide hydrolase (sEH), an enzyme that converts EETs to their inactive diols (dihydroxyeicosatrienoic acids; DiHETEs). The expression of the ovary-selective sEH isoform was restricted to the periovulatory period. Biochemical properties of the novel ovary- selective sEH will be determined, including substrate specificity, KM/Vmax, capacity to metabolize EETs and subcellular localization. The presence of a homologous primate isoform(s) will be analyzed by rapid amplification of cDNA ends (RACE). Recent studies have demonstrated that in non-ovarian cells EETs increase the expression of prostaglandin H synthase-2 (PGHS-2), a prostaglandin (PG) synthetic enzyme critical for optimal ovulatory efficiency. The major EET species produced in the ovary during the periovulatory interval will be analyzed in vitro with respect to their ability to directly induce PGHS-2 expression. In vivo effects on PGHS-2 expression, PG production, and ovulation will be determined by using inhibitors of EET generation and metabolism. These studies will provide insight into the action and regulation of EETs in the ovulatory follicle and may yield novel approaches for the regulation of fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042000-04
Application #
6884863
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Taymans, Susan
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$321,975
Indirect Cost
Name
Oregon Health and Science University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Edelman, Alison B; Jensen, Jeffrey T; Doom, Carmen et al. (2013) Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception 87:352-7
Shaw, Kate A; Hennebold, Jon D; Edelman, Alison B (2013) Effect of a combined estrogen and progesterone oral contraceptive on circulating adipocytokines adiponectin, resistin and DLK-1 in normal and obese female rhesus monkeys. Contraception 88:177-82
Stouffer, Richard L; Bishop, Cecily V; Bogan, Randy L et al. (2013) Endocrine and local control of the primate corpus luteum. Reprod Biol 13:259-71
Bogan, Randy L; Debarber, Andrea E; Hennebold, Jon D (2012) Liver x receptor modulation of gene expression leading to proluteolytic effects in primate luteal cells. Biol Reprod 86:89
Bishop, C V; Bogan, R L; Hennebold, J D et al. (2011) Analysis of microarray data from the macaque corpus luteum; the search for common themes in primate luteal regression. Mol Hum Reprod 17:143-51
Peluffo, Marina C; Murphy, Melinda J; Baughman, Serena Talcott et al. (2011) Systematic analysis of protease gene expression in the rhesus macaque ovulatory follicle: metalloproteinase involvement in follicle rupture. Endocrinology 152:3963-74
Xu, Fuhua; Stouffer, Richard L; Muller, Jorg et al. (2011) Dynamics of the transcriptome in the primate ovulatory follicle. Mol Hum Reprod 17:152-65
Letra, A; Menezes, R; Fonseca, R F et al. (2010) Novel cleft susceptibility genes in chromosome 6q. J Dent Res 89:927-32
Hennebold, Jon D (2010) Preventing granulosa cell apoptosis through the action of a single microRNA. Biol Reprod 83:165-7
Edelman, Alison B; Jensen, Jeffrey T; Hennebold, Jon D (2010) A nonhormonal model for emergency contraception: prostaglandin synthesis inhibitor effects on luteal function and lifespan, a pilot study. Contraception 81:496-500

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