# Placental Mediated Mechanisms of Perinatal Brain Injury

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

Summary
 In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and long-term disability
in children. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with
inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. CHORIO contributes to preterm CNS
injury, and is also a common, independent risk factor for brain injury in term infants, including perinatal stroke.
However, the molecular mechanisms mediating inflammation in the placenta-fetal-brain axis that cause PBI
remains a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor (CXCR2) have
been clinically implicated in CHORIO, and are essential to neutrophil recruitment, neural cell development and
adult CNS injury, although their specific role in PBI pathophysiology is completely undefined. We propose to
use our established and unique model of CNS injury associated with CHORIO to delineate how in utero
inflammation precipitates PBI. Our central hypothesis is that CXCL1 secreted by the choriodecidua during
CHORIO enters fetal blood, transcends the placenta-fetus-fetal brain axis, and through interactions on
CXCR2+ neural cells and neutrophil recruitment, confers injury in the developing CNS. We posit that CHORIO
is defined by excess CXCL1/CXCR2 signaling, which is toxic to neural cells over an extended
neurodevelopmental period. To investigate this hypothesis we will: 1) Test that CHORIO disturbs
CXCL1/CXCR2 signaling throughout the placenta-fetus-fetal brain axis during a critical period of late gestation
CNS development; 2) Test that placental CXCL1 translocates to the fetal brain and modulates neutrophils and
microglia; and 3) Test that attenuation of CXCL1/CXCR2 signal transduction protects neural cells following
CHORIO. Using multiplex electrochemiluminescent immunoassay (MECI), flow cytometry (FC), and qPCR we
will investigate whether CHORIO induced CXCL1/CXCL2 signaling is a unifying inflammatory signal
transduction mechanism through the placenta-fetus-fetal brain axis. Using in vitro assays, including exosome
analyses, placental explants and acute brain slices, we will drive CXCL1/CXCR2, and define the major
molecular mediators of damage to the placenta-fetus-fetal brain axis. Using immunoneutralization, microRNA,
pharmacological (SB225002), and genetic (CXCR2 KO) approaches, we will delineate whether CXCL1/CXCR2
is necessary and sufficient for immune cell recruitment to the CNS following CHORIO. We predict creating a
transient CXCR2 deficiency following CHORIO will attenuate microglial activation and neutrophil recruitment,
mitigate white matter and neuronal injury, and improve microstructural coherence on magnetic resonance
imaging. These investigations will be the first to connect aberrant CXCL1/CXCR2 signaling in the placenta-
fetal-brain axis to chronic injury and impaired neurodevelopment, and will define novel targets for directed
therapies for infants at high risk for PB...

## Key facts

- **NIH application ID:** 9897609
- **Project number:** 5R01HL139492-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** LAUREN Leigh Cooney JANTZIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897609

## Citation

> US National Institutes of Health, RePORTER application 9897609, Placental Mediated Mechanisms of Perinatal Brain Injury (5R01HL139492-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897609. Licensed CC0.

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