Document Type

Theses, Masters

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

Medicinal chemistry

Publication Details

Successfully submitted for the award of Master of Philosophy to the Technological University Dublin, June, 2009.

Abstract

The formation and development of ovarian follicles is regulated by the interactions of germ cells and somatic cells, intraovarian growth regulatory factors and the pituitary gonadotrophins, FSH and LH. Despite the fact that granulosa cells of large follicles are highly proliferative, granulosa cell tumours are rare suggesting that potent regulatory mechanisms, including apoptotic factors, control proliferation and differentiation of these cells. Two critical pathways that intercommunicate to influence ovarian cell proliferation and differentiation are the PI3K1AKT/FOXOI pathway and the Ras/Raf/MEKIERK cascade. As FSH can stimulate both pathways, a super-ovulatory regimen of hormones PMSG/hCG (FSHlLH analogues) administered to immature wildtype mice allowed the investigation of key components in these pathways at different stages of follicular development. In this project cell cycle regulators and apoptotic markers were investigated to determine the role they play in ovarian development. Specific PI3K and Ras pathway components were studied to decipher how they behaved throughout follicular growth. Results indicated that the exact phosphorylation and expression pattern of proteins from these pathways happens in a very transient, coordinated and timely way. Granulosa cell culture work displayed that extracellular ligands as well as FSH have the ability to stimulate both the PI3K pathway and the Ras pathway in quite a time-dependent manner. The transcription factor CEBPP is present from once hCG is administered to 5 days post hCG treatment suggesting it plays a role at many stages of follicular development as well as at the corpora lute a regression stage. Some mutant mouse models were investigated to detennine the importance of key components in the PI3K pathway and the Ras pathway. This novel insight into normal ovarian development suggests that it is the specific time dependent expression and cross talk of these pathway components that ultimately results in the coordinated and synchronised growth of immature follicles to the corpora lute a stage.

DOI

https://doi.org/10.21427/D7SG7T

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