Although progress has been made in understanding the individual roles of follicle stimulating hormone (FSH) an luteinizing hormone (LH) in governing the process of preovulatory folliculogenesis, a major question which remains unanswered is the elucidation of the intracellular signaling pathways utilized by FSH and LH in their regulation of the complex pattern of gene expression that occurs during follicular development. The research proposed herein will make use of replication-defective adenovirus vectors to explore the signaling pathways involved in granulosa cell proliferation and differentiation. Because these vectors infect granulosa cells and direct the expression of proteins with high efficiency it is possible to express constitutively activated as well as dominant-negative signaling proteins and directly assess their influences on granulosa cell steroidogenesis and cAMP production as well as the expression of mRNAs that encode for differentiation and proliferation-associated proteins.
Aim 1 will elucidate the mechanism by which FSH activates the PI3- kinase/PKB intracellular signaling pathway in granulosa cells.
Aim 2 will identify downstream effectors of PI3-kinase/ PKB signaling system in granulosa cells that govern granulosa cell differentiation.
Aim 3 will determine if LRH-1 and/or SF-1 are necessary and sufficient for cAMP-induced expression of mRNAs for enzymes involved in progesterone, but not estrogen, production during granulosa cell differentiation and to determine if SF-1 and LRH-1 are equally effective in this regard and Aim 4 will identify the intracellular signaling pathways responsible for the synergistic role of activin in FSH-stimulated granulosa cell proliferation. Understanding the intracellular signaling pathways utilized by the FSH receptor and the LH receptor will be instrumental for the development of the next generation of contraceptives as well as the next generation of """"""""fertility drugs"""""""" in which FSH and LH signaling pathways are targeted directly. In addition, results may provide new information regarding signaling pathways that may be affected in PCOS.
| Escamilla-Hernandez, Rosalba; Little-Ihrig, Lynda; Orwig, Kyle E et al. (2008) Constitutively active protein kinase A qualitatively mimics the effects of follicle-stimulating hormone on granulosa cell differentiation. Mol Endocrinol 22:1842-52 |
| Escamilla-Hernandez, Rosalba; Little-Ihrig, Lynda; Zeleznik, Anthony J (2008) Inhibition of rat granulosa cell differentiation by overexpression of Galphaq. Endocrine 33:21-31 |
| Saxena, Deeksha; Escamilla-Hernandez, Rosalba; Little-Ihrig, Lynda et al. (2007) Liver receptor homolog-1 and steroidogenic factor-1 have similar actions on rat granulosa cell steroidogenesis. Endocrinology 148:726-34 |
