FAS ANTIGEN AND OVARIAN CELL APOPTOSIS

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The overall goal is to identify triggering events and molecular mechanisms regulating programmed cell death of ovarian cells. The Fas antigen is a transmembrane receptor which triggers apoptosis (a form of programmed cell death). The project will define the role of the Fas antigen in ovarian follicular atresia and luteolysis. The specific aims are: (A) Determine Fas antigen and Fas ligand mRNA expression in specific cell types in the ovary of the cycling mouse using in situ hybridization. Quantify changes in levels of expression of Fas antigen during induction of follicular and corpus luteum development and regression using RT-PCR and flow cytometry. (B) Study modulation of expression of Fas antigen in vitro by various mediators of follicular and luteal cell differentiation and degeneration (gonadotropins, growth factors and cytokines). Effects of these agents on sensitivity of cells to Fas antigen-mediated apoptosis will be determined. The Fas antigen is expressed in human granulosa/luteal cells and engagement of the receptor with an anti-Fas antigen monoclonal antibody (Fas mAB) induces apoptosis. These results provide a rationale for studying a potential role of the Fas antigen in triggering follicular atresia and/or luteolysis. Ovarian follicles are stimulated to leave the resting stage and begin to grow by an undefined mechanism beginning before birth and continuing throughout life. Commitment of a follicle to the growth pathway is irreversible and results in one of two possible endpoints: ovulation or degeneration. Less than 1% of the follicles present in the ovary are destined to ovulate while the vast majority become atretic (degenerate) at some state in the developmental process. Following ovulation follicular cells differentiate and form the corpus luteum. The corpus luteum has a limited life-span terminating in degeneration. The factors initiating follicular atresia and luteolysis are poorly understood. Recent evidence that follicular atresia and luteolysis occur by apoptosis has provided new insight into these processes. An understanding of follicular atresia and luteolysis is essential to allow development of improved methods of fertility control, treatment of infertility and enhancement of fertility. Understanding pathways that induce apoptosis in ovarian cells may lead to development of novel therapies for ovarian and other cancers. Furthermore, the ovary provides an excellent and unique model for the study of apoptosis since continual cycles of apoptosis occur within a single organ throughout life. This laboratory has the facilities and expertise in ovarian physiology and molecular biology to undertake these studies.