# Project-001

> **NIH NIH U19** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $502,927

## Abstract

Epithelial cells are the first line of defense as they interface with the environment and initiate the response to
environmental triggers. Thus, dysregulation at the level of the epithelial cell may profoundly affect subsequent
development of allergic inflammation and disease. Defining the key epithelial cell derived drivers of persistent
immune dysregulation that lead to persistence and progression of allergic inflammation is the focus of this
application. Eczema or atopic dermatitis (AD) has been highlighted as the first step in the “atopic march”,
whereby AD typically predates the development of other allergic disorders later in life. It has been estimated
that one-third to half of patients with AD will develop asthma, however the mechanisms that promote disease
progression remain unclear. KIF3A (kinesin family member 3A) has recently emerged as an asthma and AD
susceptibility gene. Our published and unpublished data demonstrate that (1) genetic variants in KIF3A locus
are associated with childhood asthma, and this is specifically evident among children with current or previous
AD; (2) 28% of KIF3A SNPs create or destroy a CpG site in the KIF3A gene, and the prevalence of these CpGSNPs
is further enriched among asthma-associated KIF3A SNPs (p<0.001); (3) KIF3A expression is
significantly decreased in airway epithelial cells from children with severe acute asthma and in the lesional skin
of children with AD; and (4) homozygous or heterozygous deletion of Kif3a exon 2 in airway epithelial cells
results in increased susceptibility and severity of allergen-induced asthma in mice confirming a direct role for
KIF3A. Collectively, these data strongly suggest that KIF3A promotes the development of lung disease in
children with atopic dermatitis and may be a key mechanistic link in promoting crosstalk between the skin and
airway epithelium. Our central hypothesis is that there are distinct endotypes of AD that are predictive of
asthma development, that KIF3A contributes to the progression of atopic dermatitis to asthma by driving
persistent immune dysregulation and propagation of allergic inflammation, and that the contribution of KIF3A to
asthma in mediated in part by CpG-SNPs that alter gene methylation. This application will have significant
public health impact. Through the proposed aims, we will (1) delineate immunologic, clinical, physiologic,
genetic, genomic, epigenetic, and environmental factors that promote disease progression from AD to asthma;
(3) elucidate the mechanistic role of KIF3A in the progression of AD to asthma; and (4) provide the foundation
for development of new algorithms to accurately predict the development of asthma among children who have
early life AD.

## Key facts

- **NIH application ID:** 10226687
- **Project number:** 5U19AI070235-15
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Gurjit K. Khurana Hershey
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,927
- **Award type:** 5
- **Project period:** 2006-07-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226687

## Citation

> US National Institutes of Health, RePORTER application 10226687, Project-001 (5U19AI070235-15). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10226687. Licensed CC0.

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