The objectives of this proposal are to assess the role of the early stages of ascending reproductive tract infection (i.e. choriodecidual infection) in the initiation of maternal and fetal inflammatory responses that activate mechanisms of inflammation and injury in the fetal brain. The central hypothesis is that maternal-fetal inflammatory responses following choriodecidual infection with U. parvum initiate early processes of preterm labor, prior to microbial invasion of the amniotic cavity, leading to the appearance of ?sterile? fetal inflammation and brain injury. The experimental paradigm [utilizes a chronically catheterized pregnant rhesus monkey model of choriodecidual inoculation] with Ureaplasma parvum at 105dGA (term~168 days). We predict this novel approach will mimic the natural course of ascending intra-uterine Ureaplasma infection during human pregnancy, providing a model of infection-driven fetal inflammation, without direct microbial exposure of the fetus. This will allow us to assess the [initiation of fetal inflammatory responses.] Preliminary data of co- localization of hyaluronic acid with microgliosis suggests a novel mechanism by which perinatal inflammatory brain injury is mediated. [Aspects of the preterm labor syndrome will be assessed to determine how inflammatory mediators that lead to cervical ripening fetal membrane weakening and uterine contractility may also affect the developing brain.] Histological assessments will determine the extent of deciduitis, chorioamnionitis, and membrane structure and integrity. [Abdominal ultrasound and Bishop score will be employed to determine cervical shortening and dilation, respectively.] Continuous physiological monitoring of uterine pressure and serial sampling of amniotic fluid and maternal blood will occur via indwelling catheters implanted at surgery. Pro-inflammatory mediator expression (cytokines, prostaglandins, MMPs) will be measured in these samples, as well as in cord blood, fetal CSF and fetal brain and lung tissue. At delivery, fetal brains will be examined for gross pathological changes and histologic evidence of inflammation and injury. Specific markers for oligodendrocyte maturation and microglial activation will be identified and correlated to MRI findings and location of hyaluronic acid accumulation. Hyaluronic acid receptor and metabolite expression will also be determined by immunohistochemistry. Major strengths of the proposal lie in the unique non-human primate model of Ureaplasma choriodecidual infection based on preliminary data. This application and the associated career development plan will provide a foundation for the Candidate?s continued independent research in the fields of perinatal and reproductive biology. [Formal tuition in biostatistics, research design, lab management/leadership coupled with specific training in neuroscience techniques, non-human primate research skills and membership of the Brain & Behavioral Development research group part of the OHSU Center for Developmental Health and the Neurodegeration Journal Club formalize opportunities for training, scientific exchange and career development].
Premature birth is a significant obstetrical problem that is associated with fetal brain injury and a high risk of later-life neurological and behavioral deficits. This proposal will expand our understanding of the role of maternal-fetal infection in initiating the neuroinflammatory mechanisms that result in fetal brain injury.
| Ellery, Stacey J; Kelleher, Meredith; Grigsby, Peta et al. (2018) Antenatal prevention of cerebral palsy and childhood disability: is the impossible possible? J Physiol 596:5593-5609 |
| Hirsch, Alec J; Roberts, Victoria H J; Grigsby, Peta L et al. (2018) Zika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology. Nat Commun 9:263 |
| Kelleher, Meredith A; Liu, Zheng; Wang, Xiaojie et al. (2017) Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection. Pediatr Res 82:244-252 |
