# Toll-like Receptors and Respiratory Microbiota Interactions in Idiopathic Pulmonary

> **NIH NIH R00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $248,999

## Abstract

PROJECT SUMMARY/ABSTRACT
Toll-like receptor and respiratory microbiota interactions in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a lethal disease with no known cure, unknown etiology and poorly
understood pathogenesis. It is an emerging global health issue with an estimated 5 million people affected
worldwide and 17,000 deaths in the United States annually. The advent of culture-independent microbial
identification techniques has identified a respiratory microbiome associated with several lung diseases. Novel
clinical observations using bronchoalveolar lavage (BAL) fluid from IPF patients support a role for the
respiratory microbiome, both changes in community members and overall burden (dysbiosis) in disease
progression and mortality. Innate immune mediators including Toll-like receptors (TLR) have reported
associations with clinical outcomes in IPF, highlighting the previously underappreciated role of host defense in
IPF pathogenesis. However, the precise role of the respiratory microbiome and host interaction in pulmonary
fibrosis is poorly understood. The central hypothesis of this project is that dysbiosis promotes progressive lung
fibrosis through stimulation of TLRs to modulate cell-specific fibrotic responses. The specific objective is to
employ techniques from microbial ecology, bioinformatics, cell biology and animal modeling (including germ
free and gnotobiotic models) to determine the role of dysbiosis in regulating lung pathophysiology in pulmonary
fibrosis. The long term goal is to understand the role of host-microbiota interactions in the pathogenesis of IPF
and design specific therapeutic strategies for patients based on an improved understanding. In order to
achieve this objective, established animal models of pulmonary fibrosis in germ free and conventional mice
with or without antibiotic manipulation of the microbiota will be studied initially to understand the role of
dysbiosis, the host innate immune and defense response and to identify microbes associated with
experimental pulmonary fibrosis to guide gnotobiotic studies. Subsequent studies of experimental fibrosis in
animal models deficient in TLRs associated with the recognition of Gram positive (Toll-like receptor 2) and
Gram negative bacteria (Toll-like receptor 4) will further define microbiota-host interactions. Dr. O’Dwyer has
experience in TLR signaling and fibrosis and has previously published in this area. His career development
plan is focused on further mentored training in animal modeling and the bioinformatics of microbial ecology.
This project will be undertaken within the University of Michigan’s Medical School through the Department of
Internal Medicine, Department of Microbiology and Immunology and the University’s Host Microbiome Initiative.
These state-of-the-art studies will identify candidate organisms associated with fibrosis, characterize
microbiota-host (TLR) interactions that drive fibrogenesis and will highlight the crucial role that...

## Key facts

- **NIH application ID:** 10080752
- **Project number:** 5R00HL139996-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Noel O'Dwyer
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10080752

## Citation

> US National Institutes of Health, RePORTER application 10080752, Toll-like Receptors and Respiratory Microbiota Interactions in Idiopathic Pulmonary (5R00HL139996-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10080752. Licensed CC0.

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