# Investigating the CDC42 pathway as a novel pathway for pediatric non-atopic obesity-related asthma

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $491,841

## Abstract

ABSTRACT
Non-atopic or Th2-low asthma is now recognized as a major subgroup of pediatric asthma. Obesity-related
asthma, the most commonly reported form of pediatric non-atopic asthma, is associated with high disease
burden, worse lung function, and lack of response/resistance to medications. Thus, there is an urgent need to
investigate the immunobiology of non-atopic asthma to identify novel therapeutic targets. We and others have
previously reported non-atopic immune responses in peripheral blood from obese asthmatic children, with
elevated TH1/ TH2 ratio and increased TNF, IL-6, IFNγ, and IP-10 that correlated with pulmonary function
deficits in obesity-related asthma. Using RNA-Seq, we probed the biology of non-atopic responses in un-
stimulated obese asthmatic CD4+ (TH) cells and found upregulation of several genes (DOCK5, VAV2,
CDC42EP4, PAK3, MLK3 and PLD1) in the Cell Division Cycle 42 (CDC42) pathway. Higher CDC42EP4 and
DOCK5 gene expression correlated with worse airway obstruction in obese asthmatic children. Phosphorylated
p38, downstream of MLK3, and linked with steroid resistance in asthma, was higher in stimulated obese
asthmatic TH cells. Small interfering RNA (siRNA)-mediated CDC42 silencing in TH cells led to lower IFNγ and
TNF, but not IL-4, gene expression. Together, these results suggest a novel role for the CDC42 pathway in
non-atopic inflammation in obesity-related asthma. Based on these observations, we hypothesize that in
obese asthmatics, upregulation of the CDC42 pathway in a non-TH2 TH cell, which is enriched in the
airway, and activation of CDC42-regulated signaling pathways, contribute to steroid resistance and
disease burden. To test our hypothesis, we will identify the non-TH2 TH cell with CDC42 pathway upregulation
and quantify activation of CDC42-regulated signaling pathways in obese asthmatics. We will investigate
enrichment of the non-TH2 TH cell in peripheral blood in 50 non-atopic obese asthmatics as compared to 50
non-atopic normal-weight asthmatics, 50 obese non-asthmatics, and 50 healthy controls. Enrichment of the
non-TH2 TH cell in the airway will be investigated in a subset of 20 obese asthmatics and compared to 20
normal-weight asthmatics. Absent or attenuated cytokine suppression in the non-TH2 TH cell in response to
dexamethasone will provide evidence that the cell is steroid resistant and gain of steroid sensitivity following
CDC42 and/or CDC42-regulated signaling pathway inhibition will support a role of CDC42 in steroid resistance
in non-atopic asthma. To identify the contribution of obesity, and of factors other than obesity, we will compare
the findings in non-atopic obese asthmatics to obese non-asthmatics. Lastly, to link CDC42 activation with
disease burden, we will identify a biochemical signature predictive of CDC42 activation, and investigate its
contribution to disease burden in pediatric non-atopic obesity-related asthma. These studies will confirm a role
of CDC42 pathway in the immunobi...

## Key facts

- **NIH application ID:** 9873008
- **Project number:** 7R01HL141849-02
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Deepa Rastogi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $491,841
- **Award type:** 7
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873008

## Citation

> US National Institutes of Health, RePORTER application 9873008, Investigating the CDC42 pathway as a novel pathway for pediatric non-atopic obesity-related asthma (7R01HL141849-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873008. Licensed CC0.

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