The major focus of this proposal is to understand the antiproliferative/tumor suppressive properties of prohibitin, a gene located on human chromosome 17q21 close to the BRAC 1 locus. The prohibitin gene was first identified in resting, but not in dividing mammalian cells. It has been shown to have antiproliferative activity in eucaryotic cells and has been associated functionally with processes such as development, cell cycle regulation, cell senescence, differentiation, and cellular immortalization. Despite its apparent ubiquitous nature, the function of prohibitin within the mammalian system has not been elucidated. Recent studies by the PI have demonstrated that prohibitin expression is associated with cellular differentiation and apoptosis of granulosa cells during ovarian folliculogenesis and in a conditionally immortalized granulosa cell line, RGA-l. The goal of this proposal to determine the functional significance of prohibitin during granulosa cell development. The applicant hypothesizes, therefore, that over-expression of prohibitin will induce arrest in ovarian follicular growth and enhance cellular differentiation. Accordingly, he will characterize the expression pattern, regulation and function of this gene.
In Specific Aim 1, the applicant will define the spatial, temporal and cellular expression pattern of prohibitin during proliferation, differentiation and apoptosis of granulosa cells.
In Specific Aim 2, he will determine the role of cyclic AMP in the regulation of prohibitin in granulosa cells.
In Specific Aim 3, he will examine whether prohibitin over-expression inhibits granulosa cell development using a preantral follicle culture model. Lastly, in Specific Aim 4 he will characterize the spatial and temporal expression patterns of prohibitin in a non-human primate ovary model. Clearly, from a clinical perspective, an understanding of prohibitin gene involvement in ovarian somatic cell growth and differentiation during the normal physiological development of ovarian follicles is important. This understanding could potentially lead to development of novel strategies for diagnostic or prognostic therapeutics in the treatment of ovarian dysfunction, such as ovarian cancer, and in the design of a more rational basis for drug development.
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