# Respiratory sphingolipid synthesis involved in airway hyperreactivity and viral-triggered asthma

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $837,786

## Abstract

PROJECT SUMMARY
Asthma results from a complex interplay between genetic background and environmental
triggers. The 17q21 asthma susceptibility locus is strongly linked to childhood asthma through
ORMDL3. ORMDL3 regulates serine-palmitoyl CoA transferase (SPT), the critical enzyme for
the de novo synthesis of sphingolipids. We demonstrated that decreased SPT activity leads to
airway hyperreactivity. There has since been increasing evidence that sphingolipid metabolism
is altered in airway epithelial cells and animal models of ORMDL3-associated asthma. We have
recently shown that children with asthma have decreased sphingolipid synthesis, especially in
the presence of asthma risk 17q21 genotypes. 17q21 genotypes are also linked to the risk of
developing asthma following respiratory infections with human rhinovirus (HRV). This is relevant
as HRV is also the most common trigger for asthma attacks.
Supported by preliminary data in mice and airway epithelial cells demonstrating strong
similarities in sphingolipid levels and gene expression between HRV infection and sphingolipid
deficiency, we hypothesize that HRV infection can further impair sphingolipid synthesis. We
propose to study the effects of HRV on sphingolipid synthesis in children with asthma and
airway epithelial cells. These studies could then further solidify the central role of sphingolipids
in asthma pathogenesis that has been predicted by the commonality and the strong association
of 17q21 genotypes to asthma. Two specific aims are proposed to assess the overall hypothesis
that the sphingolipid de novo synthesis pathway is critical not only for asthma pathogenesis but
also in response to the most common trigger for asthma attacks. In Aim 1, we will determine
sphingolipid synthesis in the respiratory tract in children with asthma and HRV infection.
Sphingolipids will be assessed in nasal fluid, blood, and gene expression in nasal cells obtained
from children during and after the resolution of HRV-triggered asthma attacks. In a subaim, we
will evaluate the effects of HRV on sphingolipid metabolism and gene expression in primary
human airway epithelial cells (HAEC) with homozygous for a common 17q21 asthma variation
that leads to decreased blood sphingolipids in children with asthma. HAEC from an established
biorepository from adult donors and nasal brushings from children all grown at air-liquid
interface will be infected with HRV and RSV and evaluated for effects on sphingolipid synthesis.
For Aim 2, we will test the hypothesis that the altered ratio of the sphingolipid mediator
sphingosine 1-phosphate and sphinganine 1 phosphate, which we found in SPT deficiency and
children with the 17q21 asthma risk genotypes, leads to airway hyperreactivity. Overall, these
studies not only inform on the role of sphingolipids in the pathogenesis of asthma and the
relation to its most common trigger but may lead to new therapeutic approaches involving
sphingolipid metabolism.

## Key facts

- **NIH application ID:** 10782544
- **Project number:** 5R01AI171390-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Stefan Worgall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $837,786
- **Award type:** 5
- **Project period:** 2023-02-08 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782544

## Citation

> US National Institutes of Health, RePORTER application 10782544, Respiratory sphingolipid synthesis involved in airway hyperreactivity and viral-triggered asthma (5R01AI171390-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10782544. Licensed CC0.

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