# Mechanism of Bilirubin-induced Apnea in Preterm Infants

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $241,500

## Abstract

Elevated free bilirubin (Bf) in preterm newborns is a major global cause of long term
neurodevelopmental disability but the mechanisms of injury are still unclear. Bf in preterm infants
has been associated with episodic cessation of breathing, which if exceeds 15 sec is called apnea
of prematurity. Collectively, these apneic spells lead to intermittent hypoxemia, ultimately resulting
in poor neurodevelopmental outcomes. The neurons of the nucleus tractus solitarius (nTS) are
an essential part of the neural circuitry governing respiratory drive including CO2 chemosensitive
neurons, peripheral chemoreceptors and mediating responses to peripheral hypoxia. In the
preterm newborn, the nTS of the brain is undergoing rapid development: Neurons are
differentiating and extending neurites, forming synapses and undergoing myelination. These
processes depend on dynamic microdomains of the plasma membrane called lipid rafts. Lipid
rafts regulate activity of ion channels, signal transduction and protein trafficking. We hypothesize
that Bf disrupts lipid rafts leading to perturbations in the nTS, and that choline, a known
neuroprotectant, reduces the impact of Bf on both lipid rafts and apnea. With our previously
funded R21, we developed an animal model of hyperbilirubinemia of prematurity using the Gunn
rat which lacks the ability to conjugate bilirubin to glucuronide and thus excrete it. We discovered
that 1) elevated Bf disrupts the function of a lipid raft associated protein both in vitro and ex vivo,
and alters cerebellar mediated behaviors, and that 2) choline confers resistance to the effects of
Bf on both the lipid raft associated protein and behaviors. These results have put us in a position
to accomplish the following novel and clinically relevant goals: 1) explore the effects of Bf on lipid
rafts in the nTS and associated nuclei involved in respiration, and their response to choline, 2)
determine the impact of elevated Bf with or without choline on neuron excitability in the nTS and
3) measure respiratory drive and how it is impacted by Bf and choline. We predict that lipid raft
dysfunction will precede changes in neuronal excitability and respiratory drive, and all changes in
outcomes will be lessened by choline. The attainment of these goals will lead to clinical trials using
choline to try to reduce the morbidity associated with elevated Bf in human preterm infants.

## Key facts

- **NIH application ID:** 10373330
- **Project number:** 1R21HD105071-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** CYNTHIA FRANCES BEARER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $241,500
- **Award type:** 1
- **Project period:** 2021-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373330

## Citation

> US National Institutes of Health, RePORTER application 10373330, Mechanism of Bilirubin-induced Apnea in Preterm Infants (1R21HD105071-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10373330. Licensed CC0.

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