# Ependymal Dysfunction in Neonatal Post-Hemorrhagic Hydrocephalus

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $511,015

## Abstract

Project Summary
Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is a significant cause of morbidity and
mortality in preterm infants, with 14,000 new cases each year in the United States. Forty percent of severe GMH-
IVH infants have poor outcomes and 25% require long-term treatment for post-hemorrhagic hydrocephalus
(PHH), the most common cause of hydrocephalus in North America. Although the link between IVH and PHH is
well established, the underlying pathophysiology of PHH is incompletely understood and there are no
preventative treatments. Blood breakdown products, iron and hemoglobin, released in the ventricle after IVH
result in injury to the cilia-lined ependyma and cause hydrocephalus. While treatment with iron chelation reduces
hydrocephalus after IVH, it is unknown how iron and hemoglobin result in ventricular enlargement and
ependymal injury. Expression of the hemoglobin-haptoglobin receptor, CD163, is increased after IVH in the
ventricular ependyma and may represent an important route of cellular iron uptake leading to injury. We have
also demonstrated that the only known cellular iron exporter, ferroportin 1 (FP1), is expressed on ependymal
cells and subsequently upregulated in response to IVH. The ependyma is lined by motile cilia, which are
implicated in cerebrospinal fluid flow, and primary cilia, which regulate and direct neural precursor cells at the
ventricular surface. Genetic models of both motile and primary cilia dysfunction demonstrate abnormal
cerebrospinal fluid (CSF) flow and hydrocephalus; however, cilia function has not been evaluated in PHH. We
have demonstrated iron-induced cilia injury and dysfunction after IVH. The objective of this proposal is to
determine the relationship between iron-induced ependymal injury, cilia dysfunction and hydrocephalus. We will
test the central hypothesis that iron transport through CD163 and inhibition of iron export through FP1 at the
ventricular surface results in ependymal, subventricular zone (SVZ) and cilia injury, leading to defects in
ependymal development and regional CSF flow, culminating in hydrocephalus. We will test our hypothesis in the
following Specific Aims: 1) Determine whether CD163 mediates iron-induced ependymal and SVZ injury and
hydrocephalus after GMH-IVH. 2) Determine the role of FP1 in iron-mediated ependymal and SVZ injury and
hydrocephalus after grade III and grade IV GMH-IVH. 3) Determine the role of iron chelation in CSF outflow after
GMH-IVH and identify how cilia dysfunction contributes to iron-mediated ependymal cell injury, CSF flow and
hydrocephalus by inactivating postnatal ependymal cilia movement. If successful, these experiments will provide
novel targets for prevention of PHH and provide new insight into how cilia dysfunction contributes to
hydrocephalus.

## Key facts

- **NIH application ID:** 10093158
- **Project number:** 5R01NS110793-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jennifer Strahle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $511,015
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093158

## Citation

> US National Institutes of Health, RePORTER application 10093158, Ependymal Dysfunction in Neonatal Post-Hemorrhagic Hydrocephalus (5R01NS110793-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093158. Licensed CC0.

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