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

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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.