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和体外 Wnt/β- 激素调节的重要性 衣原体感染的连环蛋白信号传导。 项目概要 激素、雌激素和黄体酮水平的自然波动会改变以下情况的发生和/或严重程度 性传播感染（STI）。据估计，全球有 1.5 亿女性使用激素避孕药 含有合成雌激素和/或黄体酮的组合。沙眼衣原体每年导致 1,400,000 例 感染在美国仍然是世界上最常见的细菌性传播感染。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）管腔和腺上皮细胞。如果不加以治疗，这些生物体可能会上升到 FGT，在受感染的女性中引发盆腔炎、不孕症和宫外孕。临床试验， 动物模型和体外研究都表明雌激素通过多种方式增强衣原体感染 机制。类固醇激素对子宫内膜上皮细胞有直接和间接的影响， 诱导子宫内膜基质细胞释放调节子宫生长和成熟的效应分子 上皮细胞。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，这提供了独特的机会 在简化的体外环境中剖析复杂的激素/基质细胞/上皮细胞相互作用。数据来自这些 研究表明： i) 膜相关雌激素受体有助于介导沙眼衣原体 E 血清型进入 进入宿主生殖器上皮细胞； ii) 雌激素受体信号传导促进细胞内发育。 沙眼衣原体; iii) 雌激素刺激的子宫内膜基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； iv) 黄体酮拮抗雌激素的作用 衣原体发育。已发表的报告表明 Wnt/β-catenin 信号通路对于 沙眼衣原体的发展。有趣的是，雌激素激活 Wnt 信号传导，而孕激素则抑制 Wnt FGT 中的信号传输。该提案将测试两个独立但相关的假设。首先，在激素方面—— 暴露的共培养物中，雌激素激活 Wnt/β-catenin 信号传导有助于雌激素介导的 增强沙眼衣原体感染，而黄体酮则对沙眼衣原体产生负面影响 通过抑制Wnt的发育。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、传播和生殖病理学；和 ii) 确定分析雌激素受体独立信号传导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.