The overall purpose of this research is to develop a gamete-based, nonhormonal female contraceptive. The most practical approach to an oocyte-specific nonhormonal contraceptive involves targeting of the phosphodiesterase (PDE)-regulated metabolism of cyclic adenosine monophosphate (cAMP) [a central controller of meiotic resumption upstream of M-phase Promoting Factor (MPF)], or direct targeting of activators or inhibitors of MPF. The principal regulator of cAMP in the follicle is PDE3. Cyclic guanosine monophosphate (cGMP) [produced in cumulus granulosa cells of the follicle, and transported to the oocyte via gap junctions] is an endogenous inhibitor of PDE3. PDE5 is the principal cGMP-degrading enzyme in follicle cells, and PDE9 is the only cGMP-degrading enzyme in the oocyte. The oocyte-specific protein kinase WEE2 is an essential regulator of MPF necessary for resumption of meiosis and for exit from metaphase II following fertilization. Our research plan is to develop and test inhibitors of these targets in nonhuman primates and to ultimately perform a contraceptive trial in macaques.
The Specific Aims are: (1) To develop novel PDE and WEE2 inhibitors and determine if selected agents can disrupt timely meiotic maturation of the macaque oocyte;(2) To evaluate the pharmacoklnetics and pharmacodynamics of existing and novel PDE inhibitors and WEE2 inhibitors;and (3) To determine whether PDE and WEE2 inhibitors can function as contraceptive agents in regularly cycling macaques in group-mating situations. Experimental designs will include characterization of drug-target interactions, rational inhibitor design, high throughput screening and medicinal chemistry (Aim 1);testing of candidate agents for activity in vitro using incubation, in vitro fertilization, and intracytoplasmic sperm injection of macaque oocytes (Aim 1);Assessment of pharmacokinetic and phamacodynamic effects of candidate inhibitors in macaques in vivo with optimization of drug delivery (e.g. oral, vaginal ring, implant) systems and monitoring of non-target effects (Aim 2);and then conducting a contraceptive experiment in socially-housed female macaques (Aim 3). This approach is expected to establish the potential for PDE and WEE2 inhibitors as contraceptive agents for women.
Current contraceptive methods do not meet the needs of all couples, and concerns regarding the safety of hormonal methods are a barrier to use for some women. The development of highly effective nonhormonal methods of contraception would add to the mix of available methods and improve acceptability. This would result in increased contraceptive use, and reduce the number of unintended pregnancies, abortions, and unwanted births.
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|Peluffo, Marina C; Hennebold, Jon D; Stouffer, Richard L et al. (2013) Oocyte maturation and in vitro hormone production in small antral follicles (SAFs) isolated from rhesus monkeys. J Assist Reprod Genet 30:353-9|
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|Keator, Christopher S; Mah, Kuni; Slayden, Ov D (2012) Alterations in progesterone receptor membrane component 2 (PGRMC2) in the endometrium of macaques afflicted with advanced endometriosis. Mol Hum Reprod 18:308-19|
|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|
|Keator, Christopher S; Mah, Kuni; Ohm, Lindsay et al. (2011) Estrogen and progesterone regulate expression of the endothelins in the rhesus macaque endometrium. Hum Reprod 26:1715-28|
|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|
|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|
|Peluffo, Marina C; Barrett, Susan L; Stouffer, Richard L et al. (2010) Cumulus-oocyte complexes from small antral follicles during the early follicular phase of menstrual cycles in rhesus monkeys yield oocytes that reinitiate meiosis and fertilize in vitro. Biol Reprod 83:525-32|
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