# Mechanisms of tachykinergic nerve-mediated severe bronchoconstriction and inflammation

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $769,599

## Abstract

Project Summary
Substance P is a sensory nerve tachykinin neuropeptide capable of inducing bronchoconstriction and
inflammation. We have recently shown that airway sensory nerve density and neuronal substance P expression
are significantly increased in humans with eosinophilic asthma. We have also demonstrated that mice born to
allergen-sensitized mothers or transgenic mothers with elevated interleukin-5 (a primary cytokine involved in
eosinophil maturation and survival) recapitulate key features of human asthma including increased airway
sensory nerve density and substance P expression. When these offspring are exposed to allergen, they develop
lethal bronchoconstriction that is rescued by antagonists of substance P's target, neurokinin-1 receptors. The
central hypothesis of this proposal is that increased airway substance P innervation causes lethal
bronchoconstriction and potentiates eosinophilic inflammation after allergen challenge. In this proposal,
we will determine the mechanism by which substance P mediates these effects using both cre-recombinase and
pharmacologic methodology to 1) test the role of NK1 receptors on specific airway nerve subtypes (sensory and
parasympathetic nerves) and smooth muscle 2) test the role of NK1 receptors and a novel substance P receptor,
MrgprA1, on airway dendritic cells and 3) test the role of NK1 receptors on airway eosinophils both in isolation,
and synergistically with CCR3 (the target of eotaxin, a potent eosinophil chemoattractant). Endpoints include
measurement of airway responsiveness in vivo, eosinophil and dendritic cell activation using flow cytometry, and
quantitative assessments of airway nerve density, substance P expression, and eosinophil and dendritic cell
interactions with nerves using novel 3D confocal microscopy developed by our group. Results will identify novel
pathways and drug targets in severe asthma.

## Key facts

- **NIH application ID:** 10979522
- **Project number:** 1R01HL171226-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Matthew G. Drake
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $769,599
- **Award type:** 1
- **Project period:** 2024-06-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979522

## Citation

> US National Institutes of Health, RePORTER application 10979522, Mechanisms of tachykinergic nerve-mediated severe bronchoconstriction and inflammation (1R01HL171226-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979522. Licensed CC0.

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