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激素调节 Wnt/β-连环蛋白信号对衣原体感染的重要性。

• 批准号: 9224026
• 负责人: Jennifer LeAnn Hall
• 金额: $ 7.4万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-22 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224026
• 关键词: American; Animal Model; Antibodies; Bacteria; Cell Communication; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Clinical; Clinical Trials; Coculture Techniques; Complex; Data; Development; Diagnostic tests; Disease Progression; Ectopic Pregnancy; Effectiveness; Endometrial; Endometrial Stromal Cell; Environment; Epithelial Cell Proliferation; Epithelial Cells; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Extracellular Matrix; Female; Female of child bearing age; Future; Genital system; Goals; Gonadal Steroid Hormones; Growth; Health; Homologous Gene; Hormonal; Hormonal Change; Hormones; In Vitro; Infection; Infertility; Knockout Mice; Mammalian Oviducts; Mediating; Membrane; Menstrual cycle; Modeling; Mus; Organism; Pathology; Pathway interactions; Patients; Pelvic Inflammatory Disease; Play; Predisposition; Progesterone; Proteins; Publishing; Receptor Signaling; Reporting; Research Personnel; Role; Severities; Sexually Transmitted Diseases; Signal Pathway; Signal Transduction; Stromal Cells; System; Testing; Treatment Efficacy; Vagina; WNT Signaling Pathway; Woman; age group; beta catenin; data modeling; experimental study; female reproductive system; genital infection; hormonal contraception; in vitro Model; in vivo; inhibitor/antagonist; insight; knock-down; male; monolayer; pathogen; polarized cell; receptor; reproductive; reproductive tract; steroid hormone; transmission process; xenoestrogen

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.

确定体内雌激素受体和Wnt/β-受体的体外激素调节的重要性 连环蛋白信号转导在衣原体感染中的作用 项目摘要 激素、雌激素和孕激素的自然波动水平改变了子宫内膜异位症的发生和/或严重程度。 性传播感染（STIs）。据估计，全世界有1.5亿妇女使用激素避孕药。 含有合成雌激素和/或孕酮的组合。C.沙眼每年造成140万人 在美国感染，仍然是世界上最常见的细菌性STI。非侵入性的， 传播C。沙眼血清型D-K是专性细胞内病原体，主要在 女性生殖道（FGT）腔上皮细胞和腺上皮细胞。如果不加以治疗，这些生物体可以 FGT，引起盆腔炎，不孕症和异位妊娠感染的妇女。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， 机制等类固醇激素对子宫内膜上皮细胞有直接和间接的作用， 诱导子宫内膜基质细胞释放调节子宫内膜生长和成熟效应分子 上皮细胞以前，我们研究了激素对子宫内膜衣原体感染的影响， 上皮细胞（石川，IK）/基质细胞（SHT-290）共培养系统，其提供了独特的机会， 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。数据从这些 研究表明：i）膜相关雌激素受体有助于介导C. E型沙眼 进入宿主生殖器上皮细胞; ii）雌激素受体信号传导促进C. 雌激素刺激的子宫内膜间质细胞分泌效应物，间接帮助细胞内 生殖器上皮细胞中的衣原体发育，和; iv）孕酮拮抗雌激素对 衣原体发育已发表的报告表明，Wnt/β-catenin信号通路对于 C.沙眼发育有趣的是，雌激素激活Wnt信号传导，而孕激素抑制Wnt FGT中的信令。本提案将检验两个独立但相关的假设。首先是荷尔蒙 暴露的共培养物中，Wnt/β-catenin信号的雌激素激活有助于雌激素介导的 增强C.沙眼衣原体感染，而孕酮负作用C。沙眼衣原体 通过抑制Wnt来实现。第二，体内衣原体感染的建立和/或进展 在缺乏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; ii）确定分析雌激素受体非依赖性信号传导对衣原体感染的影响的可行性。 体内感染。