# Isoprenoid Biology in Asthma: Proof-of-Principle and Method Development

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $78,500

## Abstract

PROJECT SUMMARY
We have discovered a role for the mevalonate (MA) pathway lipid metabolites known as isoprenoids in mediating
type 2 inflammation in asthma disease models. This finding is novel and emerges from work previously
accomplished in my K08 award, and establishes the MA pathway as integral to allergic eosinophilic inflammation
in asthma. Our preliminary data show that excess pools of the isoprenoid molecules known as
farnesylpyrophosphate (FPP) and geranylgeranyl-PP (GGPP) markedly augment interleukin-13-induced STAT6
activation and eotaxin-2 and -3 production in human airway epithelial cells in vitro, key molecular pathways in
Th2/type 2 inflammation in asthma. Further, inhibition of FPP and GGPP synthesis with HMG-CoA reductase
inhibitors (‘statins’), the enzyme that synthesizes MA upstream of the isoprenoids, inhibits IL-13-induced eotaxin
production and extracellular secretion. The eotaxins being a major chemokine for eosinophil recruitment into
airway tissues, our results suggest that high levels of airway isoprenoids mediate and promote type 2 eosinophilic
airway inflammation. Furthermore, our in vivo data using mouse models of asthma, confirm the critical role of
the MA pathway in mediating allergic eosinophilic inflammation. Depleting MA pharmacologically, and therefore
the downstream metabolites FPP and GGPP, significantly inhibits lung and airway eosinophilia. While these data
are suggestive of their role in disease pathogenesis, they are limited to human airway epithelial cell culture and
mouse models of asthma. Via this R03 proposal, we wish to establish the role of isoprenoids in human disease
and ultimately determine if excess levels of airway mucosal isoprenoids correlate with degree of persistent airway
eosinophilic inflammation in asthma. Therefore to address this gap in knowledge, we hypothesize that excess
levels of airway epithelial isoprenoids enhance type 2 eosinophilic inflammation in vivo by further inducing
epithelial JAK/STAT6 phosphorylation. We will address this hypothesis via two specific aims: (1) To determine if
high levels of exogenous airway isoprenoids augment eosinophilic airway inflammation in vivo. (2) To validate a
quantitative method of measuring airway and lung isoprenoids using specialized mass spectrometry in pre-
existing animal and human tissues. Accomplishing these goals will establish the proof-of-principle that excess
isoprenoids in vivo play a role in disease pathogenesis, and most importantly, provide the tools necessary to
apply this technology to human asthmatics in future grant R01 grant applications.

## Key facts

- **NIH application ID:** 10015331
- **Project number:** 5R03HL148486-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Amir A. Zeki
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,500
- **Award type:** 5
- **Project period:** 2019-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015331

## Citation

> US National Institutes of Health, RePORTER application 10015331, Isoprenoid Biology in Asthma: Proof-of-Principle and Method Development (5R03HL148486-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10015331. Licensed CC0.

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