The proposed research is directed toward developing a better understanding of the mechanisms that control ovarian follicle development and growth, in particular the manner by which hormones and locally- produced ovarian substances regulate this process. Emphasis is placed on the elucidation of mesenchymal-epithelial cell interactions between theca cells and granulosa cells. Previous research and preliminary studies have demonstrated that the mesenchymal derived theca cells produce transforming growth factor-alpha (TGFalpha) and keratinocyte growth factor (KGF) that can act on granulosa cells. Preliminary studies have also demonstrated that the epithelial derived granulosa cells produce ckit ligand (KL) (i.e. stem cell factor) that can act on theca cells and stromal-interstitial cells. THE HYPOTHESIS TESTED IS THAT THE HORMONAL CONTROL OF OVARIAN FOLLICLE GROWTH AND DEVELOPMENT IS MEDIATED BY MESENCHYMAL-EPITHELIAL CELL INTERACTIONS BETWEEN THECA CELLS AND GRANULOSA CELLS THROUGH THE LOCAL PRODUCTION AND ACTION OF TGFalpha, KGF, and KL. The granulosa production of KL is postulated to be involved in the recruitment of theca cells from the stromal-interstitial cell population to the follicle during early development and subsequently influence theca growth and differentiation. The theca cells responding to KL will in turn produce TGFalpha and KGF that will promote granulosa cell growth and follicle cell expansion. The experimental approach consists of the following specific aims.: 1) Investigate the developmental and hormonal (i.e. LH and estrogen) regulation of mesenchymal (i.e. theca) factor, transforming growth factor-alpha (TGFalpha), and keratinocyte growth factor (KGF), expression and action; 2) Investigate the developmental and hormonal (i.e. gonadotropins) regulation of epithelial (i.e. granulosa) factor, ckit ligand (KL) (i.e. stem cell factor), expression and action; and 3) investigate the physiological importance of TGFalpha, KGF and KL expression and action. Completion of these specific aims will extend previous observations and provide insight into the role that TGFalpha, KGF, and KL may have in regulating ovarian cell proliferation and follicle development. The control of follicle growth is anticipated to be indirectly mediated through the differential effects of hormones on the production of TGFalpha, KGF, and KL. Observations are anticipated to provide insight into the molecular and cellular control of ovarian physiology.
