Diversity Supplement: Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta - Revision - 1

多样性补充：胎盘特异性 miR-519c 介导的人胎盘免疫耐受诱导 - 修订版 - 1

• 批准号: 10833899
• 负责人: Nazeeh N Hanna
• 金额: $ 5.43万
• 依托单位: NYU LONG ISLAND SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10833899
• 关键词: 3-Dimensional; Address; Affect; American; Anti-Inflammatory Agents; Bacterial Toxins; Binding; Biogenesis; Cells; Chemical Structure; Chemicals; Chronic; Data; Development; Dose; Endotoxins; Environment; Environmental Exposure; Environmental Health; Environmental Impact; Enzyme-Linked Immunosorbent Assay; Equilibrium; Exposure to; Failure; Fetus; Flame Retardants; Future; Genetic; Goals; Grant; Health; Host Defense; Hour; Household; Human; Immune; Immune Tolerance; Immunosuppression; In Vitro; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Invaded; Literature; Maternal-Fetal Exchange; Mediating; Mentors; MicroRNAs; Microfluidics; Modeling; Molecular; Molecular Toxicology; Mothers; Mus; Organism; Parents; Pathogenesis; Pathologic; Placenta; Placentation; Predisposition; Pregnancy; Pregnancy Outcome; Pregnancy Trimesters; Premature Birth; Production; Research; Research Personnel; Role; Serum; Signal Transduction; Stimulus; Sum; System; Techniques; Tissues; Toxic Environmental Substances; Toxicant exposure; Training; Translational Research; Woman; chemical stability; cytokine; developmental toxicology; digital; doctoral student; environmental chemical exposure; experience; exposed human population; extracellular vesicles; fetal; in vitro Model; innovative technologies; interest; maternal stress; nanoparticle; new technology; novel; organ on a chip; parent grant; pathogen; polybrominated diphenyl ether; prevent; reproductive; trophoblast; 3-Dimensional; Address; Affect; American; Anti-Inflammatory Agents; Bacterial Toxins; Binding; Biogenesis; Cells; Chemical Structure; Chemicals; Chronic; Data; Development; Dose; Endotoxins; Environment; Environmental Exposure; Environmental Health; Environmental Impact; Enzyme-Linked Immunosorbent Assay; Equilibrium; Exposure to; Failure; Fetus; Flame Retardants; Future; Genetic; Goals; Grant; Health; Host Defense; Hour; Household; Human; Immune; Immune Tolerance; Immunosuppression; In Vitro; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Invaded; Literature; Maternal-Fetal Exchange; Mediating; Mentors; MicroRNAs; Microfluidics; Modeling; Molecular; Molecular Toxicology; Mothers; Mus; Organism; Parents; Pathogenesis; Pathologic; Placenta; Placentation; Predisposition; Pregnancy; Pregnancy Outcome; Pregnancy Trimesters; Premature Birth; Production; Research; Research Personnel; Role; Serum; Signal Transduction; Stimulus; Sum; System; Techniques; Tissues; Toxic Environmental Substances; Toxicant exposure; Training; Translational Research; Woman; chemical stability; cytokine; developmental toxicology; digital; doctoral student; environmental chemical exposure; experience; exposed human population; extracellular vesicles; fetal; in vitro Model; innovative technologies; interest; maternal stress; nanoparticle; new technology; novel; organ on a chip; parent grant; pathogen; polybrominated diphenyl ether; prevent; reproductive; trophoblast

SUM M ARY/ABSTRACT Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring the balance between immunosuppression, essential for maintaining semi-allogeneic fetus and pro-inflammatory host defense to protect the mother and fetus from invading organisms. Adaptation to repeated inflammatory stimuli may be critical in preventing the rejection of the fetus by the exaggerated maternal inflammatory responses to mild/moderate infections that are common during human pregnancy. This adaptation suppresses an overly aggressive inflammatory response to repeated infections that can be detrimental to the tissues rather than protective. Our data point to the involvement of a human and placenta-specific miRNA called miRNA-519c-3p (miR-519c) in the development of placental immune tolerance. Our overriding hypothesis of the parent RO1 grant (titled: Placenta-specific miR-519c-mediated induction of immune tolerance in human placenta, 5T R01- HD098258-04) is that repeated exposure of the placenta to pathogens will induce a tolerant phenotypemediated by the placenta-specific miR-519c to guard the maternal-fetal interface from the exaggerated inflammation associated with pathologic pregnancies. • Aim 1: Investigate the role of placenta-specific miR-519c in mediating immune adaptation in the human placenta after repeated bacterial toxin challenges. • Aim 2: Investigate the molecular mechanisms of placental miR-519c mediatingimmune tolerance. This supplement proposal seeks support for Ms. Rahanna Khan, a second-year Ph.D. student with long-term goals to be an independent researcher in environmental health. Ms. Khan has focused her research interest on studying environmental impacts on reproductive and developmental health and strives to specialize in translational research within this field. Aim 1 of the parent RO1 hypothesizes that miR-519c deficiency will lead to placental immune tolerance failure resulting in infection-induced preterm birth. However, it is unclear why some women are deficient in placental miR-519c and, therefore,more susceptible to pretermbirth. The proposed supplement will examine the role of the environmental toxin polybrominated diphenyl ether 47 (PBDE-47) in decreased placental immune tolerancethrough deficient miR-519c signaling. PBDE-47 is a persistent,ubiquitous flame retardant that is correlated with the incidence of preterm birth and is detectable in the majority of American women's serum. We hypothesize that PBDE-47-treated placental cells will alter placental immune tolerance and reduce the amount of miR-519c produced in placental extracellular vesicles (EVs). The aims are as follows: • Aim 1: Determine the effects of PBDE-47 exposure on placental immune adaptation • Aim 2: Characterize the effects of PBDE-47 on placental EV-miR-519c production. This study may elucidate a novel mechanism by which PBDE-47 exposure contributes to human preterm birth through reduced miR-519c expression and provide an in vitro alternative model for future mechanistic studies.

总和/摘要 怀孕代表了母亲 - 狂热免疫接口的独特挑战，需要在 免疫抑制作用，对于维持半合法胎儿和促炎的宿主防御至关重要 保护母亲和胎儿免于入侵生物。适应反复的炎症刺激可能是 通过夸张 在人类怀孕期间常见的轻度/中度感染。这种适应会抑制过度 对重复感染的侵略性炎症反应，这些感染可以确定为组织而不是 保护的。我们的数据指向人类和胎盘特异性miRNA的参与，称为miRNA-519c-3p （miR-519c）在lopenal免疫耐受性的发展中。我们对父母RO1的压倒性假设 赠款（标题：胎盘特异性miR-519c介导的人胎盘免疫耐受性诱导，5T R01-- HD098258-04）是，在病原体上反复暴露于病原体会诱导耐受的表型抑制 由PLACETA特定的miR-519c来保护夸张的注入孕产妇界面 与病理妊娠有关。 •AIM 1：研究胎盘特异性miR-519c在介导免疫加热中的作用 重复细菌毒素挑战后的人胎盘。 •目标2：研究胎盘miR-519c介导免疫耐受性的分子机制。 该补充提案寻求支持Rahanna Khan女士的支持。长期的学生 成为环境健康独立研究人员的目标。汗女士将她的研究兴趣集中在 研究环境对生殖和发展健康的影响，并努力专门研究 该领域的翻译研究。母体RO1的目标1假设miR-519c缺陷将导致 为了使人的免疫力衰竭导致感染引起的早产。但是，目前尚不清楚为什么 一些妇女缺乏斑点miR-519c，因此更容易受到早产的影响。提议 补充剂将检查环境毒素多溴二苯基乙醚47（PBDE-47）在 下部免疫耐受性miR-519c信号传导降低。 PBDE-47是持久的无处不在的 与早产事件相关的阻燃剂，大多数美国人都可以检测到 女性精华素。我们假设PBDE-47处理的斑点细胞将改变斑点免疫耐受性，并且 减少斑点外蔬菜（EV）中产生的miR-519c的量。目的如下： •AIM 1：确定PBDE-47暴露对位置免疫适应的影响 •AIM 2：表征PBDE-47对Placenal EV-MIR-519C生产的影响。 这项研究可能阐明了一种新型机制，PBDE-47暴露有助于人类早产 通过降低miR-519c表达，并为将来的机械研究提供了体外替代模型。