# Project 1: Metabolic Interventions and Biomarkers of Activated Eosinophils in Asthma Control

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $673,264

## Abstract

ABSTRACT – PROJECT 1
Disease-modifying or personalized preventive strategies for asthma remain elusive. Project 1 puts forward two
aims to achieve these goals under the overarching hypothesis that pathologic oxidant mechanisms are central
to pathogenesis of asthma. First, Project 1 proposes the concept of metabolic endotypes of asthma and
investigates whether diet can modulate inflammatory responses, gene expression, and airway hyperreactivity.
Our Cycle I studies indicate that cellular metabolism and oxidative potential are different in asthmatics as
compared to healthy controls, and that Coenzyme Q administration re-establishes normal redox, suggesting
mitochondrial mechanisms in the dis-equilibrium. In an early phase study, an alternate day diet ablates the
classical TH2 gene expression signature present during standard American diet, and a subgroup of asthmatics
lose hyperreactivity to methacholine. Preliminary data show mitochondrial DNA haplotypes that have greater
uncoupling of oxidative phosphorylation carry asthma risk. In aim 1, we test the hypothesis that alternate day
caloric restriction benefits asthma through mechanisms that decrease oxidative metabolism, TH2 gene
expression, and pro-inflammatory TH17 signaling pathways. We also test the complementary idea that
mitochondrial haplotypes that confer asthma-risk may influence response to diet intervention. We propose to
test these ideas through a longitudinal mechanistic trial: Metabolic Intervention to Reverse Asthma (MIRA).
Second, Project 1 proposes to advance utility of urine bromotyrosine (BrTyr), a biomarker of oxidative-
modifications produced by the activated eosinophil, as a major step forward to a personalized medicine
strategy in asthma, in particular for application of biologically-based treatments. In Cycle I, we showed that
BrTyr levels increase during asthma exacerbation, and high levels identify patients with poor control and at-risk
of exacerbation. In preliminary studies, BrTyr is quantitatively related to asthma severity, and levels decrease
in proportion to the improvement in FEV1 with parenteral corticosteroids. In aim 2, we test the hypothesis that
BrTyr will: (1) identify clinical responders to a TH2-targeted anti-IgE intervention in a longitudinal trial of BrTyr
in Treatment Effectiveness of asthma [BrYTE]; and (2) be quantitatively related to asthma severity and control
in collaborative studies with NIH asthma networks, industry studies, and in MIRA. Project 1 depends on
expertise and resources of the program to establish mechanisms within clinical studies: Project 2 for TH17
mechanisms in metabolism and asthma, and Project 3 for biochemical mechanisms of airway hyperreactivity.
Core A enables sharing of Project 1 clinical samples in order to facilitate translational and mechanistic
experiments. Project 1 through Core B support has forged strong partnerships (Nestlé, Procter & Gamble,
Novartis, and Cleveland HeartLab) to implement strategies and products. The f...

## Key facts

- **NIH application ID:** 9986006
- **Project number:** 5P01HL103453-10
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Serpil C. Erzurum
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $673,264
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986006

## Citation

> US National Institutes of Health, RePORTER application 9986006, Project 1: Metabolic Interventions and Biomarkers of Activated Eosinophils in Asthma Control (5P01HL103453-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986006. Licensed CC0.

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