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

摘要 妊娠对母胎免疫界面是一个独特的挑战，需要平衡 免疫抑制，维持半同种异体胎儿和促炎宿主防御， 保护母亲和胎儿免受入侵生物的侵害。对反复炎症刺激的适应可能是 在防止胎儿排斥反应的夸大母体炎症反应， 轻度/中度感染是人类怀孕期间常见的。这种适应抑制了过度的 对反复感染的侵袭性炎症反应，可能对组织有害，而不是 保护性的我们的数据表明，一种名为miRNA-519 c-3 p的人类胎盘特异性miRNA参与了这一过程。 （miR-519 c）在胎盘免疫耐受的发展中的作用。我们对母体RO 1的首要假设 格兰特（标题：胎盘特异性miR-519 c介导的人胎盘免疫耐受诱导，5 T R 01- HD 098258 -04）是胎盘反复暴露于病原体将诱导耐受性表型介导的 通过胎盘特异性miR-519 c保护母胎界面免受过度炎症的影响， 与病理性妊娠有关。 ·目的1：研究胎盘特异性miR-519 c在介导免疫适应中的作用。 在反复细菌毒素挑战后的人胎盘。 目的2：探讨胎盘miR-519 c介导免疫耐受的分子机制。 这一补充提案寻求对博士二年级学生Rahanna Khan女士的支持。学生长期 目标是成为一名独立的环境健康研究人员。Khan女士将她的研究兴趣集中在 研究环境对生殖和发育健康的影响，并努力专注于 在这个领域的翻译研究。亲本RO 1的目的1假设miR-519 c缺陷将导致 胎盘免疫耐受失败导致感染诱导的早产。然而，目前还不清楚为什么 一些妇女胎盘miR-519 c缺乏，因此更容易早产。拟议 补充报告将研究环境毒素多溴联苯醚47（PBDE-47）在 通过缺乏miR-519 c信号降低胎盘免疫耐受。PBDE-47是一种持久的、普遍存在的 阻燃剂与早产的发生率相关，并且在大多数美国人中可检测到。 女人的血清我们假设PBDE-47处理的胎盘细胞会改变胎盘的免疫耐受性， 减少胎盘细胞外囊泡（EV）中产生的miR-519 c的量。其目标如下： ·目标1：确定PBDE-47暴露对胎盘免疫适应的影响 ·目标2：表征PBDE-47对胎盘EV-miR-519 c产生的影响。 这项研究可能阐明一种新的机制，PBDE-47暴露有助于人类早产 通过减少miR-519 c表达，并为未来的机制研究提供体外替代模型。

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.