TUMOR NECROSIS FACTOR AND FOLLICLE DEVELOPMENT

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The overall objective of the proposed research is to further our understanding of ovarian development in the fetus and neonate, and specifically to investigate the role of tumor necrosis factor-alpha (TNF) in follicle differentiation and steroidogenesis. TNF has recently been implicated in the development of ovarian cancer, yet it also has cytotoxic effects against other types of cancer. It is hoped that defining the role of TNF in normal development will lead to an understanding of abnormal states such as infertility and ovarian cancer. This research is especially important because clinical trials involving TNF as a cancer-fighting agent have been initiated; and further trials utilizing anti-TNF strategies have been suggested. Thus, understanding the normal physiological role of TNF strategies have been suggested. Thus, understanding the normal physiological role of TNF on reproductive parameters is critical. Previous research has shown that TNF appears in rat oocytes around the time of birth; therefore the first specific aim is to specifically pinpoint the time that TNF and its mRNA arise in the rat oocyte. The second aim is to determine which of the two TNF subtypes is present within the fetal and neonatal rat ovary, in an effort to determine whether TNF can be correlated with developmental events. The third specific aim is to test the hypothesis that TNF is necessary for normal follicle differentiation. The strategy that will be used is to neutralize TNF by using TNF antisense oligonucleotides in an ovarian organ culture system and observing effects on follicle differentiation in vivo. The final specific aim is to test the hypothesis that TNF will significantly affect the development of steroidogenic capacity of the neonatal rat ovary. No previous work has been done ot clarify effect of TNF in the neonatal ovary; however, previous studies on various adult ovarian cell types have demonstrated that TNF affects gonadotropin-stimulated, rather than basal steroid production. Therefore, the effect of TNF on basal and gonadotropin-stimulated progesterone and estradiol production will be determined using a dispersed ovary culture system. The proposed studies are essential to direct future studies on the function of ovarian TNF in the perinatal time period.