# Cerebrospinal Fluid Dynamics in Posthemorrhagic Hydrocephalus in Neonates

> **NIH NIH R01** · LOMA LINDA UNIVERSITY · 2021 · $345,625

## Abstract

Abstract
Germinal matrix hemorrhage (GMH) is the bleeding from the thin-walled immature blood vessels in the
germinal matrix of pre‑term infants. Post‑hemorrhagic hydrocephalus is a common but severe consequence
from GMH. However, there is no effective treatment for this so far but surgical shunting, which causes a huge
socioeconomic burden. Thus, to characterize the underlying mechanisms and identify the potential therapeutic
targets are of the utmost importance. Cerebrospinal fluid (CSF) is mainly produced from the choroid plexus
and reabsorbed by subarachnoid villi and to a greater extent in neonates, through the glymphatic system. GMH
results in breakdown of blood products, inflammation and astrogliosis, which can damage periventricular
tissues. Tissues responsible for maintaining normal CSF flow dynamics may be injured following GMH,
contributing to post-hemorrhagic hydrocephalus. The choroid plexus is specialized for CSF production and
regulating the blood-CSF barrier. Iron toxicity from lysed red blood cells after GMH may lead to increased
expression of slc4a10, a sodium bicarbonate co-transporter responsible for CSF secretion, and consequent
CSF over-secretion at the choroid plexus. Furthermore, glymphatic CSF drainage is postulated to play a great
role in neonates, since subarachnoid villi are sparsely distributed, and its function may also be compromised
following GMH. The glymphatic system involves astrocyte-mediated CSF-interstitial fluid (ISF) exchange in
Virchow-Robin space, which is driven by astrocytic aquaporin-4. In addition, inwardly rectifying potassium
channel 4.1 (Kir4.1) works in conjunction with aquaporin-4 in astrocytes for regulating osmotic gradients and
consequent water flow, yet its role in glymphatic CSF-ISF exchange has not been established. Astrogliosis
from GMH may alter aquaporin-4 and Kir4.1 expression or function, disrupting glymphatic CSF-ISF exchange
and consequently reducing CSF reabsorption. Our overall hypothesis is that, following GMH, acute iron
overload contributes to CSF overproduction at the choroid plexus by inducing slc4a10 and long-term
astrogliosis impairs normal CSF reabsorption through the glymphatic system, leading to post-
hemorrhagic hydrocephalus in neonates. To test this hypothesis, we will conduct our study in two specific
aims. Specific Aim 1: Determine the role of iron-induced expression of slc4a10 at the choroid plexus
after GMH, leading to increased CSF secretion. Specific Aim 2: Determine the role of GMH-induced
astrogliosis and consequent Kir4.1 and aquaporin-4 expression in disrupting CSF-ISF exchange and
CSF clearance through the glymphatic system.

## Key facts

- **NIH application ID:** 10213849
- **Project number:** 5R01NS103822-05
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** John H Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,625
- **Award type:** 5
- **Project period:** 2017-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213849

## Citation

> US National Institutes of Health, RePORTER application 10213849, Cerebrospinal Fluid Dynamics in Posthemorrhagic Hydrocephalus in Neonates (5R01NS103822-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213849. Licensed CC0.

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