DESCRIPTION (provided by applicant): Premature disruption of corpus luteum (CL) function results in the prevention of pregnancy, irregular cyclicity, and an overall decrease in reproductive efficiency. In mammals, including primates and human, PGF/2alpha is believed to be the trigger that induces the regression (luteolysis) of the CL, whereby progesterone synthesis is inhibited, the luteal structure involutes, and the menstrual or estrus cycle resumes. However, despite extensive studies demonstrating its physiological role, the cellular and molecular mechanisms of PGF/2alpha-induced CL regression remain poorly understood. Our preliminary data demonstrate that the expression of Egr-1 mRNA and protein is up regulated in the CL during PGF/2alpha-induced luteolysis in vivo and in PGF/2alpha-treated luteal cells in vitro. The Egr-1 gene belongs to a group of immediate early response genes, which encode zinc finger-containing DNA-binding transcription factors. Recent studies suggest that Egr-1 may mediate molecular programs of proliferation and/or differentiation during follicle growth, ovulation, and lutenization. However, studies in various cell lines have also shown that Egr-1 protein can induce the up-regulation and activation of various pro-apoptotic proteins, suggesting that Egr-1 is an active part of the apoptotic-signaling cascade. Nevertheless, the mechanisms controlling Egr-1 expression and the role of Egr-1 in the CL are not known. We hypothesize that Egr-1 plays an important role in the action of PGF/2alpha by inducing the expression of key proapoptotic proteins and reducing progesterone secretion. Two specific aims are proposed: Specific Aim 1: To determine the cellular location and activity of Egr-1 in control and PGF/2alpha-treated bovine luteal cells. Specific Aim 2: To determine the role of Egr-1 protein in the regulation of pro-apoptotic proteins, such as PTEN, and TGFbeta1, and progesterone secretion in bovine luteal cells. By determining the regulation and function of Egr-1 in response to PGF/2alpha treatment, the proposed study will facilitate our understanding of the bio-physiology of CL regression and pathophysiology of luteal dysfunction. The completion of this study will provide valuable information in developing new therapeutic strategies for the regulation of fertility and the management of infertility caused by inadequate luteal function and/or ovarian disorders.
|Effective start/end date||12/6/04 → 11/30/07|
- National Institutes of Health: $71,773.00
- National Institutes of Health: $73,500.00
Apoptosis Regulatory Proteins