ROLE OF GLYCOSYLATION IN FSH SIGNALING IN FSH TARGET CELLS

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The gonadotropin follicle-stimulating hormone (FSH) is critical for regulating fertility and sex steroid hormone production. Positive and negative feedback systems between gonadotropins and steroid hormones are in place to finely control the reproductive processes of follicle recruitment, ovulation, corpus luteum (CL) development, maintenance, and ultimately CL regression. The aging process results in a decline in fertility and diminished sex steroid hormone levels, the latter of which has considerable metabolic consequences. The glycosylation of FSH is critical for its ability to activate FSH-responsive target cells. Recent evidence indicates that glycoform abundance is under physiological regulation; and importantly new isoforms of FSH have been characterized. Analysis of hFSH preparations revealed that di-glycosylated hFSH is more abundant than tetra-glycosylated hFSH in young women and levels of tetra-glycosylated hFSH are elevated in postmenopausal women. Furthermore, di-glycosylated hFSH appears to have much greater ability to stimulate estrogen secretion than other forms. However, little is known about the cellular signaling mechanisms that occur in granulosa cells that occur as a result of alterations in FSH glycosylation. Our preliminary data indicate that FSH can activate multiple signaling pathways in its target cells. Furthermore, our data suggest that activation of phosphatidylinositol-3-kinase/AKT signaling correlates well with aromatase expression and estrogen secretion, whereas, activation of Erk signaling reduces aromatase and estrogen production. Conversely, the activation of Erk in granulosa cells results in increased proliferative responses at the expense of steroidogenesis. This proposal will test the overall hypothesis that di-glycosylated and tetra-glycosylated hFSH glycoforms provoke qualitative and quantitative differences in cellular signaling pathways, which contribute to altered cellular responses in cells expressing FSH receptors.Aim 1. Determine the efficacy and potency of FSH glycoforms in terms of FSH receptor signaling and steroidogenesis using a homogeneous porcine ovarian granulosa cell monolayer model. Aim 2. Determine how FSH glycoforms control FSH receptor signaling, follicle growth, and steroidogenesis in a well-established whole follicle culture model. Aim 3. Determine FSH glycoform signaling and bone cell function using well-established primary cultures of bone cells and a FSH-responsive bone macrophage-cell line. The ability to employ three relevant but distinct model systems will provide a unique opportunity to discover how FSH glycoform signaling controls the function of FSH-responsive target cells.