The objective of this research proposal is to understand the hormonal regulation and tissue-specific expression of the genes encoding the inhibins and activins, gonadal proteins that play key roles in the control of FSH synthesis and secretion. Inhibin (an alpha-beta dimer) has endocrine actions on pituitary FSH secretion and is a paracrine modulator of gonadal activity, while activin (a beta-beta dimer) regulates growth and differentiation in many target tissues. The inhibin and activin alpha and beta subunit mRNAs are expressed in granulosa cells of the rodent ovary and are tightly regulated by the pituitary gonadotropins, FSH and LH. FSH stimulates inhibin subunit mRNA levels in growing follicles, while LH potently down-regulates inhibin subunit mRNA levels in mature preovulatory follicles. The proposed studies will investigate the DNA promoter elements and protein important for the hormonal regulation and cell-specific expression of the alpha and beta subunit genes in ovarian granulosa cells. There are four interrelated experimental aims. The first two aims utilize molecular and genetic approaches to investigate mechanisms whereby the preovulatory LH surge suppresses inhibin gene expression. This is a physiologically important event, in that the resulting decrease in inhibin secretion provides an environment permission to the secondary surge of FSH and recruitment of a new cohort of follicles.
Aim 1 will establish the role of inducible cAMP early repressor (ICER), a potent transcriptional repressor for several gonadotropin and cAMP-regulated genes, in the LH suppression of inhibin alpha subunit gene expression in preovulatory granulosa cells.
Aim 2 will determine if repressor forms of CAAT/enhancer binding protein-beta (C/EBPbeta), a transcription factor that plays a critical role in ovarian function, are expressed in the ovary and involved in LH regulation of inhibin alpha subunit gene expression. The third specific aim investigates regulation of the beta/alpha subunit gene, which is common to inhibin A and activin A, in granulosa cells.
Aim 3 examines the function of a novel cAMP and phorbol ester final specific aim addresses the important issue of tissue- specific expression of the inhibin alpha subunit gene in the reproductive axis.
Aim 4 will investigate the role of steroidogenic factor-1 (SF-1) in tissue specific expression of the alpha subunit gene using cell transfection and transgenic animal approaches. These studies are expected to provide insight into the regulation of inhibin and activin in the reproductive system that will facilitate understanding their involvement in reproductive diseases or dysfunctions of importance to human health.
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