Mechanisms of Endometrial Innate Immune Responses to Infection and Impact on Placental Interactions

子宫内膜对感染的先天免疫反应机制及其对胎盘相互作用的影响

• 批准号: 10269931
• 负责人: Mancy Tong
• 金额: $ 12.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269931
• 关键词: Advisory Committees; Affect; Bacterial Infections; Bioinformatics; Biology; Cell Aging; Cell Communication; Cell Differentiation process; Cell physiology; Coculture Techniques; Communication; Data; Decidual Cell Reactions; Double-Stranded RNA; Endometrial; Endometrial Stromal Cell; Endometrium; Escherichia coli; Exposure to; Family; First Pregnancy Trimester; Functional disorder; Growth; IL8 gene; Immunology; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type I; Knowledge; Learning Skill; Link; Lipopolysaccharides; Maternal-Fetal Exchange; Mediating; Mentors; Mentorship; Microbe; Phase; Placenta; Placental Biology; Placentation; Play; Poly I-C; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy loss; Premature Birth; Process; Production; Progesterone; Public Health; Receptor Signaling; Regulatory Pathway; Research; Risk; Role; Series; Signal Pathway; Signal Transduction; Simplexvirus; Testing; Therapeutic; Toll-like receptors; Training; Uterus; Viral; Virus Diseases; Woman; Work; adverse pregnancy outcome; base; chemokine; cytokine; desensitization; early pregnancy loss; experience; extracellular vesicles; failure Implantation; fetal; healthy pregnancy; immune function; immunoregulation; implantation; improved; in vivo; insight; medical schools; migration; mouse model; novel; obstetrical complication; post-doctoral training; premature; response; senescence; success; three-dimensional modeling; transcriptome sequencing; trophoblast

PROJECT SUMMARY Spontaneous pregnancy loss during the first 12 weeks of gestation is the most common obstetric complication affecting 1 in 4 women worldwide. Uterine infection is associated with ~15% of first trimester losses and a dysfunctional endometrium is suggested to play a role in ~50% of cases. Specific microbes, such as E. coli and Herpes simplex virus have also been associated with reduced implantation success, however how the endometrium responds to infection is unclear. Endometrial stromal cells (EnSCs) are the major cellular component of the endometrium that undergo decidualization monthly in anticipation of pregnancy. Decidualized EnSCs plays key roles in regulating implantation and placentation. The overall objective of this proposal is to investigate how infectious components affect EnSC decidualization and crosstalk with placental trophoblasts. Based on preliminary data, our central hypothesis is that exposure of undecidualized EnSCs to bacterial and viral components triggers inflammation and accelerates EnSC decidualization and senescence. Together, this dysregulates EnSC-trophoblast interactions, leading to impaired placentation and adverse pregnancy outcomes. Furthermore, decidualization may also reduce the sensitivity and response of EnSCs to infectious components. To test these hypotheses, the mechanisms by which non-decidualized and decidualizing EnSCs respond to bacterial and viral components will be determined (Aim 1). Then, how exposure to bacterial and viral components affect EnSC decidualization and differentiation will be examined in vitro and in vivo (Aim 2). The significance of altered EnSC function in response to infectious components will be investigated by examining their downstream interactions with trophoblasts mechanistically in vitro and functionally in vivo (Aim 3). The first two aims will enrich the candidate’s experience in endometrial biology, bioinformatic analysis and mouse models of decidualization (K99 phase). The candidate has established an expert mentoring and advisory team led by Dr. Vikki Abrahams at Yale School of Medicine to enable this training. As the candidate transitions into independence, she will combine this knowledge with her prior training in placental biology, extracellular vesicles and immunology to study whether endometrial-placental crosstalk is affected by infection (Aim 3, R00 phase). The proposed studies are significant because they will establish a novel mechanistic understanding of how infection regulates EnSC decidualization and function, directly linking infection with endometrial dysfunction, implantation failure and the myriad of obstetric complications associated with impaired placentation. Thus, these findings may contribute to the identification of novel preventative and therapeutic strategies to improve pregnancy success for women worldwide.

项目摘要 妊娠前12周自然流产是最常见的产科并发症 影响全球四分之一的女性。子宫感染与约15%的妊娠早期流产有关， 功能失调的子宫内膜被认为在~50%的病例中起作用。特定的微生物，如E.杆菌和 单纯疱疹病毒也与植入成功率降低有关，然而， 子宫内膜对感染的反应尚不清楚。子宫内膜基质细胞（Endometrial stromal cells，EnSC）是子宫内膜的主要细胞， 子宫内膜的组成部分，每月经历蜕膜化以期待怀孕。蜕膜 EnSC在调节着床和胎盘形成中起关键作用。本建议的总体目标是 研究感染性成分如何影响EnSC蜕膜化和与胎盘滋养层细胞的串扰。 基于初步数据，我们的中心假设是未蜕膜化的EnSC暴露于细菌和 病毒成分引发炎症并加速EnSC的蜕膜化和衰老。在一起，这 EnSC-滋养层相互作用失调，导致胎盘形成受损和不良妊娠结局。 此外，蜕膜化也可能降低EnSC对感染成分的敏感性和反应。 为了验证这些假设，非蜕膜化和蜕膜化EnSC响应于 将确定细菌和病毒成分（目标1）。那么，接触细菌和病毒成分 影响EnSC蜕膜化和分化将在体外和体内进行检查（目的2）。的意义 将通过检查EnSC的下游， 在体外与滋养层的机械相互作用和在体内与滋养层的功能相互作用（目的3）。前两个目标将丰富 候选人在子宫内膜生物学、生物信息学分析和小鼠蜕膜化模型方面的经验 (K99阶段）。候选人已经建立了一个由Vikki Abrahams博士领导的专家指导和咨询团队 在耶鲁大学医学院，以实现这一培训。随着候选人过渡到独立，她将 联合收割机将这些知识与她先前在胎盘生物学、细胞外囊泡和免疫学方面的培训相结合， 研究胎盘-胎盘串扰是否受感染影响（Aim 3，R 00阶段）。拟议的研究 是重要的，因为他们将建立一个新的机制，了解感染如何调节EnSC 蜕膜化和功能，直接将感染与子宫内膜功能障碍、着床失败和 与胎盘形成受损有关的各种产科并发症。因此，这些发现可能有助于 确定新的预防和治疗策略，以提高妇女的怀孕成功率 国际吧