Endometriosis is frequently associated with impaired fertility, altered ovarian function and poor oocyte quality. Increasing endocrine and clinical data indicate that acute phase genes (such as Cebpb) and inflammatory cytokines (such as IL6) are induced in non-immune cells, including ovarian cells during normal processes of development where they exert cell context specific changes in gene expression profiles and cell function. Therefore, uncontrolled expression of inflammatory cytokines/chemokines has the potential to alter the normal ovarian function and may mediate the pleotrophic consequences of elevated cytokines and chemokines associated with endometriosis. This notion is supported by the recent observations that ovarian somatic cells produce potent cytokines during the normal process of ovulation and that cytokines such as IL6 impact the endocrine functions of granulosa cells and regulate the matrix forming activities of cumulus cells surrounding the ovulated oocyte. Cytokines may also regulate the dramatic genetic reprogramming that directs the transition of granulosa cells to terminally differentiated luteal cells, a process that involves a production of specific cytokines, cell cycle arrest and terminal cell differentiation. CEBPp (CAAT enhancer binding protein beta) is linked to acute phase responses as well as cell cycle arrest. CEBPp can also impact the expression of 116. In the ovary CEBPp is induced in granulosa cells of mouse, rat and porcine preovulatory follicles by LH/hCG. Mice null for Cebpb fail to ovulate or luteinize. However, the biochemical and molecular mechanisms by which CEBPp regulates these ovarian events remains unknown. Therefore, we propose that altered expression of IL6 (and/or other cytokines) and CEBPp mediate critical events associated with ovulation and luteinization and when in excess cytokines could contribute to the impaired ovarian cell responses in patients with endometriosis.
Specific Aim I : Determine the pattern of induction and activation (phosphorylation) of CEBPp in granulosa and cumulus cells of follicles of immature mice induced to ovulate and luteinize.
Specific Aim II : Determine targets of C/EBPp that impact ovulation versus those that control the terminal differentiation of granulosa cells to luteal cells using Cebpb conditional knockout mice.
Specific Aim III : Determine the clinical relevance of CEBPp, IL6 and specific cytokines and chemokines to impaired ovarian cell function in patients with endometriosis and in mouse models of endometriosis.
Although endometriosis is estimated to affect 3-10% of young women, the etiology of this disease and the effects on ovarian function, remain ill-defined and controversial. Because endometriotic tissue releases potent cytokines/chemokines, these factors have the potential to impair oocyte quality and contribute to infertility. We propose to analyze the production and actions of cytokines during ovulation in mice and determine if women with endometriosis exhibit altered gene expression patterns in cumulus cells.
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