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

MARY/摘要和 怀孕对母婴免疫接口来说是一个独特的挑战，需要在 免疫抑制，对于维持半异基因胎儿和促炎宿主防御是必不可少的 保护母亲和胎儿免受生物入侵。对反复炎性刺激的适应可能是 在防止母体过度炎症反应引起的胎儿排斥反应中起关键作用 人类妊娠期间常见的轻度/中度感染。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 防护性的。我们的数据指出，人类和胎盘特异的miRNA参与了名为miRNA-519c-3p的研究 (MIR-519c)在胎盘免疫耐受形成中的作用。我们对亲代RO1的压倒一切的假设 Grant(标题：胎盘特异性miR-519c介导的人胎盘免疫耐受诱导，5T R01- HD098258-04)是胎盘反复暴露于病原体会诱导出耐受的表型 通过胎盘特异性miR-519c保护母胎界面免受夸大的炎症 与病理性怀孕有关。 目的1：探讨胎盘特异性miR-519c在胎盘免疫适应中的作用 人类胎盘经过反复的细菌毒素挑战。 目的2：探讨胎盘miR-519c介导免疫耐受的分子机制。 这项补充提案寻求对Rahanna Khan女士的支持，她是一名长期 目标是成为环境健康领域的独立研究人员。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，并努力专门研究 这一领域的翻译研究。亲本RO1的目标1假设miR-519c缺陷将导致 胎盘免疫耐受失败导致感染诱发早产。然而，原因尚不清楚。 一些妇女胎盘miR-519c缺乏，因此更容易早产。建议数 附录将研究环境毒素多溴二苯醚47(PBDE-47)在 通过miR-519c信号缺陷降低胎盘免疫耐受性。PBDE-47是一种持久的、无处不在的 一种与早产发生率相关的阻燃剂，在大多数美国人中都能检测到 女性血清。我们推测，经PBDE-47处理的胎盘细胞将改变胎盘免疫耐受和 减少胎盘细胞外小泡(EVS)产生miR-519c的量。目标如下： ·目标1：确定多溴联苯醚-47暴露对胎盘免疫适应的影响 目的2：研究PBDE-47对胎盘EV-miR-519c产生的影响。 这项研究可能会阐明一种新的机制，即暴露于多溴联苯醚-47导致人类早产 通过降低miR-519c的表达，为进一步的机制研究提供了体外替代模型。

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.