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: 10672601
• 负责人: Mancy Tong
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672601
• 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.

项目总结 妊娠前12周的自然流产是最常见的产科并发症。 全球每4名女性中就有1人受到影响。子宫感染与大约15%的早期妊娠损失和 在约50%的病例中，功能不全的子宫内膜被认为起作用。特定的微生物，如大肠杆菌和 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。子宫内膜间质细胞(EnSCs)是最主要的细胞 月经蜕膜化的子宫内膜成分，以备怀孕。专门化 EnSCs在调控着床和胎盘形成中起着关键作用。这项提议的总体目标是 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的EnSCs暴露于细菌和 病毒成分会引发炎症，加速EnSC蜕膜化和衰老。总而言之，这 调节EnSC-滋养层细胞的相互作用，导致胎盘受损和不良妊娠结局。 此外，蜕膜化还可能降低EnSCs对感染性成分的敏感性和反应性。 为了检验这些假说，非蜕膜化和去蜕化的EnSCs对 将确定细菌和病毒成分(目标1)。那么，接触细菌和病毒成分是如何 将在体外和体内检测影响EnSC蜕膜化和分化的因素(目标2)。的重要意义。 将通过检查其下游来研究感染成分对EnSC功能的改变 体外与滋养层细胞的机械相互作用和体内功能的相互作用(目标3)。前两个目标将丰富 应聘者在子宫内膜生物学、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 在耶鲁大学医学院进行这项培训。随着候选人过渡到独立，她将 将这方面的知识与她之前在胎盘生物学、细胞外小泡和免疫学方面的培训结合起来， 研究子宫内膜-胎盘串扰是否受感染的影响(目标3，R00期)。建议进行的研究 具有重要意义，因为它们将建立对感染如何调节EnSC的新的机制理解 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 与胎盘位置受损相关的无数产科并发症。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妊娠成功率 全世界。