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: 10687025
• 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/10687025
• 关键词: Acceleration; 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; Invaded; 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; Series; Signal Pathway; Signal Transduction; Simplexvirus; Testing; Therapeutic; Toll-like receptors; Training; Uterus; Viral; Virus Diseases; Woman; Work; adverse pregnancy outcome; 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

项目成果

Antiphospholipid Antibodies Increase Endometrial Stromal Cell Decidualization, Senescence, and Inflammation via Toll-like Receptor 4, Reactive Oxygen Species, and p38 MAPK Signaling.

• DOI: 10.1002/art.42068
• 发表时间: 2022-06
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Tong, Mancy;Kayani, Teimur;Jones, Deidre M.;Salmon, Jane E.;Whirledge, Shannon;Chamley, Lawrence W.;Abrahams, Vikki M.
• 通讯作者: Abrahams, Vikki M.