The goal of the studies proposed in this application is to elucidate the role of tumor necrosis factor (TNF) in follicular development and atresia in the rat. An antibody to human recombinant, TNF has been used to reveal the ovarian granulosa cell as a source of TNF. Human TNF has been found to stimulate follicular progesterone production in vitro. Studies proposed in this application will focus on whether TNF alters steroidogenesis of healthy and atretic follicles in an attempt to ascertain if TNF may be a trigger for the onset of follicular atresia. Using in vivo and in vitro experimental models of follicular atresia, I125-TNF binding to healthy and atretic follicles will be ascertained. Atresia will be prevented during sodium phenobarbital delayed ovulation in the rat with prolactin and the effects of TNF on follicular steroidogenesis in vitro and I125-TNF binding to follicles will be assessed. The effects of exogenous TNF in vivo on the morphology and steroidogenesis of healthy follicles will be determined. Several studies planned focus on whether the production of TNF can be hormonally regulated both in vivo and in vitro. Since TNF first appears during antrum formation, it is hypothesized that estrogen, FSH (and possibly LH) regulate its production. In addition, the effects of TNF on granulosal cell proliferation in vitro is of special interest. Since rat granulosal cells divide poorly in vitro, it is possible that this production of TNF is negatively modulating their growth. Therefore, granulosa cells will be grown in the presence of anti-TNF in order to determine whether their growth is enhanced. The discovery that TNF is present in the ovary of rat, cow and human indicates some universality of a role of TNF in its function. TNF has been shown experimentally to reduce tumor growth. The possibility exists that TNF controls the growth rate of follicles in the ovary and prevents excessive growth of these structures into cysts and tumors. However, when the ovarian TNF supply is exhausted, ovarian tumor growth may be enhanced.
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