Abnormal EMPS Expression Affects Pregnancy Outcome

描述(由申请人提供)：生殖生物学中一个关键且尚未解决的问题是子宫对胚泡的基础接受性。激素和局部信号协调子宫内膜的戏剧性变化，但相关分子的身份和这一协调事件的机制尚不清楚。我们最近在子宫上皮细胞表面发现了一种四跨膜蛋白，即上皮膜蛋白2(EMP2)，它是成功着床所必需的。我们假设，EMP2调节关键细胞表面蛋白向糖脂丰富的脂筏微域(GEM)的输送，包括对着床能力至关重要的某些整合素异构体。此外，我们预测EMP2的表达受生理刺激(孕酮)和病理生理刺激(NFkappaB诱导的炎症介质)的上调和下调。通过这种方式，我们认为EMP2为着床能力所需的适当时机的子宫上皮反应提供了一个优雅的生化开关，并为炎症介导的生育损害提供了一个病理生理学靶点。我们的目标是利用原代小鼠子宫内膜上皮和人子宫内膜细胞系来解决EMP2功能的两个重要的细胞和生化意义。在我们的第一个目标中，我们讨论了EMP2在将整合素异构体靶向于富含糖脂的表面膜结构域中的作用，以及这种靶向对整合素依赖的细胞黏附(与胚泡-子宫内膜相互作用相关的过程)的影响。在我们的第二个目标中，我们通过靶向EMP2启动子中观察到的调节元件的药物来确定对EMP2表达的控制，这些调节元件包括类固醇性激素(孕激素受体结合位点)、PPARGamma/RXR激动剂以及细胞因子IL-1β和TNFpha(靶向NFkappaB位点)。如果这些研究成功，将揭示一种控制妊娠结局的新的重要分子开关，并可能揭示避孕设计和不孕症治疗的新的药理靶点。

DESCRIPTION (provided by applicant): 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.