Determining the importance of in vivo estrogen receptors and in vitro hormone modulation of Wnt/β-catenin signaling on Chlamydia infections.

确定体内雌激素受体的重要性和Wnt/β的体外激素调节 衣原体感染中的连环蛋白信号转导。 项目摘要 荷尔蒙、雌激素和黄体酮水平的自然波动会改变卵巢癌的发生和/或严重程度 性传播感染(STI)。据估计，全球有1.5亿妇女使用荷尔蒙避孕药 含有合成雌激素和/或黄体酮的组合。沙眼衣原体每年导致140万人 在美国感染，并且仍然是全球最常见的细菌性性传播感染。非侵入性的，性的 传播的沙眼衣原体D-K血清型是专性细胞内病原体，主要在 女性生殖道(FGT)腔上皮和腺上皮细胞。如果不治疗，这些微生物可以上升到 FGT，可引起感染妇女的盆腔炎、不孕和异位妊娠。临床试验, 动物模型和体外研究都表明雌激素通过多种途径增强衣原体感染 机械装置。类固醇激素对子宫内膜上皮细胞有直接和间接作用，而且 诱导子宫内膜间质细胞释放调节子宫生长成熟的效应分子 上皮细胞。在此之前，我们研究了激素对子宫内膜衣原体感染的影响。 上皮细胞(Ishikawa，IK)/基质细胞(SHT-290)共培养系统，这为 在简化的体外环境中剖析复合激素/基质细胞/上皮细胞的相互作用。来自这些网站的数据 研究表明：1)膜相关雌激素受体有助于介导沙眼衣原体E亚型进入 2)雌激素受体信号转导促进C。 沙眼；iii)雌激素刺激的子宫内膜间质细胞分泌间接辅助细胞内的效应物 生殖器上皮细胞中衣原体的发育；以及；iv)孕酮拮抗雌激素对 衣原体发育。已发表的报道表明，Wnt/β-连环蛋白信号通路在 沙眼衣原体发育。有趣的是，雌激素激活Wnt信号，而黄体酮抑制Wnt FGT中的信号。这项提议将检验两个独立但相关的假设。首先，在激素方面- 暴露于共培养环境中，雌激素激活Wnt/β-连环蛋白信号有助于雌激素介导 增强沙眼衣原体感染，而孕酮对沙眼衣原体有负面影响 通过抑制Wnt的发育。第二，体内衣原体感染的建立和/或进展 在没有雌激素受体的情况下会受到抑制。这些实验的数据将：i)增加 了解激素如何调节衣原体感染、传播和生殖病理；以及 二)确定分析雌激素受体非依赖性信号对衣原体影响的可行性 体内感染。

Determining the importance of in vivo estrogen receptors and in vitro hormone modulation of Wnt/β- catenin signaling on Chlamydia infections. Project Summary Naturally fluctuating levels of the hormones, estrogen and progesterone, alter the occurrence and/or severity of sexually transmitted infections (STIs). An estimated 150 million women worldwide use hormonal contraceptives containing combinations of synthetic estrogen and/or progesterone. C. trachomatis annually causes 1,400,000 infections in the US and remains the most frequent bacterial STI worldwide. The non-invasive, sexually transmitted C. trachomatis serovars D-K are obligate intracellular pathogens that replicate primarily within female genital tract (FGT) luminal and glandular epithelial cells. If untreated, these organisms can ascend the FGT, evoking pelvic inflammatory disease, infertility and ectopic pregnancy in infected women. Clinical trials, animal models and in vitro studies all suggest that estrogen enhances chlamydial infection by multiple mechanisms. Steroid hormones have both direct and indirect effects on endometrial epithelial cells and also induce endometrial stromal cells to release effector molecules that regulate growth and maturation of uterine epithelial cells. Previously, we investigated the effects of hormones on chlamydial infection in an endometrial epithelial cell (Ishikawa, IK)/stromal cell (SHT-290) co-culture system, which provides a unique opportunity to dissect complex hormone/stromal cell/epithelial cell interactions in a simplified in vitro setting. Data from these studies indicate that: i) membrane-associated estrogen receptors help mediate C. trachomatis serovar E entry into host genital epithelial cells; ii) estrogen receptor signaling facilitates intracellular development of C. trachomatis; iii) estrogen-stimulated endometrial stromal cells secrete effectors that indirectly aid intracellular chlamydial development in genital epithelial cells, and; iv) progesterone antagonizes the effects of estrogen on chlamydial development. Published reports indicate that the Wnt/β-catenin signaling pathway is important for C. trachomatis development. Interestingly, estrogen activates Wnt signaling whereas progesterone inhibits Wnt signaling in the FGT. This proposal will test two independent, but related, hypotheses. First, in hormone- exposed co-cultures, estrogen-activation of Wnt/β-catenin signaling contributes to estrogen-mediated enhancement of C. trachomatis infections whereas progesterone negatively effects C. trachomatis development by inhibiting Wnt. Second, the establishment and/or progression of chlamydial infection in vivo will be inhibited in the absence of estrogen receptors. Data from these experiments will: i) increase understanding of how hormones modulate chlamydial infection, transmission and reproductive pathology; and ii) determine the feasibility of analyzing the effects of estrogen receptor-independent signaling on chlamydial infection in vivo.