# Role of ORMDL3 and ceramide in asthma severity

> **NIH NIH F31** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $15,045

## Abstract

PROJECT SUMMARY
 Susceptibility to asthma as well as its exacerbation are influenced by the environment and numerous genetic
variations. ORM (yeast)-like protein isoform 3 (ORMDL3) has been shown to be one of genetic factors of this
disease and there is a strong association between its expression and allergic asthma. Physiologically, ORMDL3
is a negative regulator of serine palmitoyltransferase (SPT), the rate-limiting enzyme in the de novo biosynthesis
of ceramide, a central sphingolipid metabolite. However, published and preliminary data from our lab has
suggested that under pathological conditions, such as asthma, upregulation of ORMDL3 unexpectedly increased
ceramide. In house dust mite (HDM) and Alternaria alternata (Alt) mouse models of allergic airway disease that
recapitulate the hallmarks of human allergic asthma, we found that both ORMDL3 and ceramide are increased
in the lung and exacerbate airway inflammation and hyperreactivity (AHR).
 The lung epithelium is the initial site of contact for inhaled pathogens and allergens and excessive apoptosis
within the lung epithelium forms cellular aggregates referred to as Creola bodies that commonly correlate with
asthma severity. Yet, little is known of the initial trigger of the apoptotic process. Interestingly, I found that not
only ceramide elevation but also apoptosis and oxidative stress (ROS) were reduced in the lung of allergen-
challenged mice treated with the SPT inhibitor myriocin (Myr). Based on the preliminary data, I hypothesize that
ORMDL3 expression is upregulated specifically in lung epithelial cells during allergic asthma, leading to dramatic
increases in sphingolipid metabolites, particularly ceramide. I suggest that this elevation of ceramide contributes
to the exacerbation of allergic asthma by inducing apoptosis and/or oxidative stress and that targeting the
ORMDL3-ceramide axis will lessen inflammation, airway obstruction, and AHR. To test this hypothesis, in Aim
1, I will examine the mechanisms by which ceramide elevation contributes to asthma exacerbation. In Aim 2, I
will investigate the role of global or cell autonomous ORMDL3 overexpression on formation of ceramide and their
functions in asthma exacerbation.
 My proposal will enhance understanding of the pathological roles of ORMDL3 and ceramide in allergic
asthma, link enhanced ceramide levels to apoptosis or oxidative stress and susceptibility of asthma, and may
pave the way for potential new therapeutic avenues for asthma.

## Key facts

- **NIH application ID:** 10328478
- **Project number:** 5F31HL154486-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Briana James
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $15,045
- **Award type:** 5
- **Project period:** 2020-08-15 → 2021-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328478

## Citation

> US National Institutes of Health, RePORTER application 10328478, Role of ORMDL3 and ceramide in asthma severity (5F31HL154486-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10328478. Licensed CC0.

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