Grants and Contracts Details
A woman’s fertility is dependent on the cascade of events leading up to ovulation. Defects in this ovulatory process result in 25% of all female infertility cases, supporting the paramount role of ovulation in reproductive success and providing a strong premise to explore mediators of the ovulatory process. We propose that neurotensin is one of these pivotal regulators of the ovulatory process, based on our findings below. Ovulation is set in motion by the preovulatory LH surge which increases ovarian intrafollicular mediators that act to bring about oocyte release. Our novel and exciting preliminary data indicate that neurotensin (NTS), a small neuropeptide, is a key intrafollicular mediator of ovulation. This is based upon our findings that NTS is one of the most differentially-expressed genes in the granulosa cells of the human ovulatory follicle, up to 15,000 fold after the ovulatory gonadotropin surge. Likewise, after hCG administration NTS mRNA rapidly and significantly increases in granulosa cells from mice ovulatory follicles. Immunodetection of NTS in ovulatory follicles from women suggest that both granulosa and theca cells synthesize NTS. Importantly, mice lacking NTS expression form luteinized unruptured follicles following LH/hCG administration, consistent with failure of ovulation. However, other than our preliminary data, nothing is known regarding the temporal expression of NTS receptors or the function of NTS in ovulation and female fertility. These questions will be addressed in this proposed study utilizing the exceptional backgrounds, technical expertise, and models of our laboratory. We will make use of a high-impact, translational model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG (early, late and postovulatory) to complement in vivo and in vitro studies performed with mice. The regulation of NTS and NTS receptor expression in the ovulatory follicle will be illuminated and compared across women and mice in Aim 1. The ovulatory functions stimulated by NTS in granulosa, theca, cumulus, and endothelial cells of the follicle will be elucidated in Aim 2. The actions of NTS on ovulation, as well as other key reproductive processes, will be revealed in mice using mice lacking NTS expression and NTS receptor antagonists in Aim 3. The present study explores the role of neurotensin in the ovulatory process. NTS increases prior to ovulation in mice and women, and a loss of NTS results in ovarian follicles that do not ovulate. The proposed studies will elucidate the role that this exquisite system plays in the coordinated processes of follicular rupture and oocyte release, which will aid in the understanding of the regulation of human fertility.
|Effective start/end date
|6/1/20 → 5/31/21
- Lalor Foundation: $52,000.00
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