RPG:Role of the Fas Antigen and Bcl-2 in Ovarian Follicular Apoptosis

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This is a research planning grant for women. Follicles in the ovary undergo a continuous process of growth and regression; only a small minority actually proceed to ovulation. Substantial evidence suggests that atresia occurs by the process of apoptosis, or programmed cell death. However, the genes controlling apoptosis are not known. The operating hypothesis of this research is that ovarian follicular apoptosis occurs in response to definable signals: either lack of a survival factor or induction by a cytotoxic stimulus. Genes coding for two proteins, the fas antigen and BCL-2, have been demonstrated to be intimately involved in apoptosis in other systems, inducing and suppressing the process, respectively. Limited data available indicate that the fas antigen is expressed in the mouse ovary and bcl-2 is expressed in the chicken ovary. The proposed preliminary research will examine the role of these genes in ovarian follicular apoptosis by studying their expression in vivo in healthy and atretic follicles of rats. Subsequent research will examine the regulation of expression of the fas antigen and bcl-2 in rat follicular cells in vitro by various mediators of follicular development. Finally, a potential cause and effect relationship between fallicular atresia and expression of these genes will be examined by inhibiting the activity or expression of the gene products using antibodies and antisense oligonucleotides to mRNA. Mammalian females are born with a full complement of germ cells, the oocytes, present in the ovary. Oocytes become surrounded by a structure called the follicle which is comprised of granulosa and theca cells. Throughout life ovarian follicles are stimulated to develop, a process involving growth and differentiation of all cell types within the follicle. Only a few of the follicles that enter the growing pool actually progress to ovulation. The vast majority begin to degenerate, or undergo atresia at different points in the developmental process. Recent evidence indicates that ovarian follicular atresia occurs by programmed cell death, an active process whereby a cell mediates its own death by following a genetically determined developmental program. Factors regulating cell death in the ovary have not been identified. This propossal will test whether genes encoding two proteins, the fas antigen and BCL-2, which are involved in inducing and suppressing programmed cell death in other systems (the immune system, nervous system and in various tumor cells) also regulate cell death in the ovary. An understanding of follicular degeneration is essential to allow development of improved methods of fertility control, treatment of infertility and enhancement of fertility. There is intense interest in programmed cell death because of its involvement in a wide variety of normal developmental processes as well as its relevance to the development of cancers. The ovary provides an excellent model for the study of programmed cell death.