# Targeting the Choroid Plexus-Cerebrospinal Fluid System to Treat Post-Hemorrhagic Hydrocephalus

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $565,326

## Abstract

PROJECT SUMMARY
Post-hemorrhagic hydrocephalus (PHH) is a leading cause of morbidity in premature infants. PHH is triggered
by germinal matrix intraventricular hemorrhage (IVH) that results in accumulation of cerebrospinal fluid (CSF) in
the brain compression of surrounding brain tissue, and permanent neurological deficits. While PHH is clearly
caused by an altered balance of CSF production and removal, the mechanisms are poorly understood, limiting
our ability to guide rational therapies. Here, we propose to examine two processes that could be manipulated
therapeutically to alleviate PHH: (1) ion and fluid transport by the choroid plexus (ChP), and (2) ventricular blood
clearance by macrophages. In adults under normal physiological conditions, sheets of specialized ChP epithelial
cells secrete CSF via an incompletely understood set of membrane proteins including NKCC1, a phosphorylation
activated bi-directional Na-K-Cl cotransporter. Strikingly, we recently discovered that NKCC1 participates in CSF
removal rather than CSF secretion during early stages of brain development. CSF-K+ levels are significantly
higher in embryos than adults, likely explaining this opposite direction of NKCC1 water transport8. Experimental
introduction of blood into the ventricles during development appears to further elevate CSF-K levels, and to drive
intracellular calcium activity in ChP epithelial cells, expression of the immediate early gene c-fos, and increased
expression/phosphorylation of NKCC1. Our findings suggest a novel counter-regulatory response to IVH in
premature infants: ChP absorption of CSF via NKCC1, driven by K+. We will test this hypothesis by determining
if NKCC1 activation either worsens or mitigates hydrocephalus in our mouse IVH model (Aim 1; preliminary data
suggests the latter). We also found that following IVH, blood products linger in the developing ventricles and may
account for the persistence of PHH. The brain's ventricles and the apical surface of the ChP are home to specific
macrophages known as Kolmer cells. While Kolmer cells have been implicated as responders to brain
hemorrhage, their scavenging and other functions have remained elusive. Our data suggest that during early
stages of brain development, ventricular macrophages/Kolmer cells are activated and recruited to the site of
blood leakage within the ventricle (Aim 2A) and that these macrophages are necessary and sufficient to clear
blood and/or inflammatory signals from the ventricles (Aim 2B, C). Collectively, our data suggest that the ultimate
severity of PHH depends on a developmental stage-specific interplay between blood products, ion
concentrations (e.g. [K]), immune and inflammatory reactions, and NKCC1 expression levels. An estimated 20%
of infants that experience intraventricular bleeds develop PHH. We suspect this is due to insufficient endogenous
compensatory responses. The ultimate goal of this proposal is to improve outcomes by laying the groundwork
for development ...

## Key facts

- **NIH application ID:** 10754974
- **Project number:** 5R01NS129823-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** MARIA LEHTINEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,326
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754974

## Citation

> US National Institutes of Health, RePORTER application 10754974, Targeting the Choroid Plexus-Cerebrospinal Fluid System to Treat Post-Hemorrhagic Hydrocephalus (5R01NS129823-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10754974. Licensed CC0.

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