# Neurotrophins in the Lung

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $617,564

## Abstract

Airway hyperreactivity (AHR) and remodeling in asthma involve increased airway smooth muscle (ASM)
contractility, mass, and extracellular matrix (ECM) driven by inflammation. ASM actively secretes growth
factors that modulate airway structure/function via autocrine/paracrine influences. In previous cycles, we
identified brain-derived neurotrophic factor (BDNF) as an ASM-derived factor with autocrine enhancement of
ASM contractility, proliferation and fibrosis. Within this purview, we discovered glial-derived neurotrophic factor
(GDNF) and a related member neurturin (NRTN) as novel growth factors in the airway that promote
inflammation effects. GDNF and NRTN have protective roles in the nervous system but there is minimal to no
information on GDNF or NRTN in airway biology or asthma, particularly for ASM. Preliminary studies show
that A) Human ASM expresses and secretes GDNF and NRTN in response to agonist, with increased release
by TNFα or TGFβ and in asthmatic ASM; B) GDNF and NRTN receptors Ret, GFRα1 and GFRα2 are present
in ASM with increased expression in inflammation/asthma; C) Exogenous GDNF and NRTN have pleiotropic
effects on ASM, enhancing [Ca2+]cyt and contractility, promoting ECM formation, and intriguingly ER stress,
mitochondrial fission, mitochondrial Ca2+ and respiration; D) GDNF and NRTN can interact via GFRα1. In vivo
studies in mixed allergen (MA) mouse models of asthma show 1) GDNF enhances airway reactivity; 2) Ret
inhibition or chelation of GDNF blunt MA effects on AHR and remodeling. Based on these data, we propose an
overall hypothesis that ASM expression and autocrine signaling by GDNF ligand family contributes to AHR
and remodeling in asthma. We will test this concept via four Aims, focusing particularly on the novel role of
ASM-derived GDNF and NRTN. Our Aims are: Aim 1: To examine mechanisms of upstream regulation of
GDNF vs. NRTN in human ASM; Aim 2: To examine mechanisms by which GDNF vs. NRTN enhance
Ca2+/contractility in human ASM in the context of inflammation and asthma; Aim 3: To examine mechanisms
by which GDNF vs. NRTN enhance remodeling in human ASM in the context of inflammation and asthma; Aim
4: To examine in vivo importance of GDNF vs. NRTN in the context of AHR and remodeling using a mixed
allergen mouse model of asthma. Aims 1-3 utilize human epithelium-denuded ASM tissues and isolated ASM
cells from mild or moderate asthmatics vs. non-asthmatics to examine signaling mechanisms by which
inflammatory mediators enhance GDNF/NRTN production (Aim 1), the receptor and intracellular pathways by
which these ligands influence contractility (Aim 2) vs. ER stress, mitochondrial structure/function and
proliferation/ECM (Aim 3). Aim 4 applies the MA model to mice where GDNF vs. NRTN is enhanced or
inhibited, particularly in smooth muscle and explores changes in airway structure, ECM composition, and
mechanics. Clinical significance lies in establishing the role of ASM-derived growth factors such as GDNF or
NRTN tha...

## Key facts

- **NIH application ID:** 9969586
- **Project number:** 5R01HL088029-10
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Y. S. Prakash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,564
- **Award type:** 5
- **Project period:** 2009-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969586

## Citation

> US National Institutes of Health, RePORTER application 9969586, Neurotrophins in the Lung (5R01HL088029-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9969586. Licensed CC0.

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