A critical and unresolved issue in reproductive biology is the basis uterine receptivity to the blastocyst. Hormonal and local signals orchestrate a dramatic change in the endometrium, but the identity of the pertinent molecules, and the mechanism of this orchestrated event, is poorly understood. We recently identified, on the surface of uterine epithelium, a four transmembrane protein, epithelial membrane protein 2 (EMP2) that is required for successful implantation. We hypothesize that EMP2 regulates the delivery of key cell surface proteins to glycolipid-enriched lipid raft microdomains (GEMs), including certain integrin isoforms critical for implantation competence. Furthermore, we predict that EMP2 expression is up- and down-regulated by physiologic (progesterone) and pathophysiologic (NFkappaB-inducing inflammatory mediators) stimuli. In this fashion, we believe that EMP2 provides an elegant biochemical switch for the properly timed uterine epithelial response required for implantation competence, and, a pathophysiologic target for inflammation-mediated impairment of fertility.
Our aims are to resolve two important cellular and biochemical implications of EMP2 function, using primary mouse endometrial epithelium and human endometrial cell lines. In our first aim, we address the role of EMP2 in targeting integrin isoforms to glycolipid-rich surface membrane domains, and the impact of this targeting on integrin-dependent cell adhesion (a process pertinent to blastocyst-endometrial interaction). In our second aim, we determine the control of EMP2 expression by agents targeting regulatory elements observed in the EMP2 promoter, including steroid sex hormones (progesterone receptor binding site), PPARgamma/RXR agonists, and cytokines IL-1beta and TNFalpha (targeting the NFkappaB site). These studies, if successful, will reveal a novel and important molecular switch to control pregnancy outcome, and may reveal new pharmacologic targets for contraception design and infertility treatment.
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