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囊胚的基础接受性。 激素和局部信号协调了子宫内膜的戏剧性变化，但相关分子的身份以及这种协调事件的机制知之甚少。我们最近发现，在子宫上皮细胞表面，一个四跨膜蛋白，上皮膜蛋白2（EMP 2），是成功植入所需的。我们推测，EMP 2调节关键的细胞表面蛋白质的糖脂富集脂筏微结构域（GEM），包括某些整合素异构体的植入能力的关键。此外，我们预测，EMP 2的表达上调和下调生理（孕酮）和病理生理（NF κ B诱导炎症介质）的刺激。以这种方式，我们认为，EMP 2提供了一个优雅的生物化学开关，为适当的定时子宫上皮细胞的反应所需的植入能力，和炎症介导的损害生育力的病理生理学目标。我们的目的是解决两个重要的细胞和生物化学的影响EMP 2功能，使用原代小鼠子宫内膜上皮细胞和人类子宫内膜细胞系。在我们的第一个目标中，我们解决了EMP 2在靶向整合素亚型的糖脂丰富的表面膜结构域的作用，以及这种靶向整合素依赖性细胞粘附（一个相关的过程胚泡子宫内膜相互作用）的影响。在我们的第二个目标中，我们确定了EMP 2表达的控制剂靶向在EMP 2启动子中观察到的调控元件，包括类固醇性激素（孕酮受体结合位点），PPARgamma/RXR激动剂，和细胞因子IL-1 β和TNF α（靶向NF κ B位点）。这些研究如果成功，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药理学靶点。

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.