# Mitochondrial DNA and TLR9 in Pulmonary Fibrosis

> **NIH NIH K08** · YALE UNIVERSITY · 2022 · $167,940

## Abstract

PROJECT SUMMARY
Candidate: My long-term career goal is to develop a successful academic career and become an independently
funded physician-scientist focused on the study of innate immunity in idiopathic pulmonary fibrosis (IPF). Under
the guidance of my mentor and research advisors, I have received training in laboratory-based assays, in vitro
models of IPF, translational medicine, and biostatistics. I have proposed career development activities that will
allow me to continue this training, but also develop unique expertise that is distinct from my mentor in the areas
of (1) innate immunity and (2) computational biology. Mentors and Environment: I will be mentored by Dr. Erica
Herzog, a globally renowned IPF investigator who has studied the immunopathogensis of fibrosis with an
extremely impressive track record of successful mentees. My advisors include Dr. Naftali Kaminski, a well-known
IPF investigator whose visionary methods in the genomic profiling of fibrotic lung disease have revolutionized
the field; Dr. Wajahat Mehal, who has been lauded for his work with mitochondrial DNA (mtDNA) and Toll-Like
Receptor 9 (TLR9) in the development of fibrosis; Dr. Min-Jong Kang, an expert in mitochondrial innate immunity
in chronic lung disease; and Dr. Anjelica Gonzalez, who has developed novel methods in bioengineering for ex
vivo modeling of the fibrotic microenvironment. My department Chair (Dr. Gary Desir) has assured me that at
least 75% of my time will be dedicated to my career development, and he and my Section Chief (Dr. Kaminski)
have detailed their commitment. Mentored Research Project: The pathogenesis of IPF involves the
uncontrolled accumulation of activated myofibroblasts, which arise in response to TGFβ1 mediated interactions
with the stiff fibrotic lung microenvironment. The innate immune receptor TLR9, which recognizes and responds
to mtDNA derived from injured cells, has been shown to have a significant role in mediating this process. We
showed that mtDNA is released by TGFβ1-stimulated and stiffness-induced normal human lung fibroblasts,
where it induces myofibroblast transformation in a manner that phenocopies fibroblasts harvested from the IPF
lung. In the clinical setting, mtDNA concentrations are elevated in the plasma of IPF subjects, where it displays
a robust association with all-cause mortality in two independent cohorts. Our subsequent studies reveal that
mice deficient in TLR9 are protected from fibrosis caused by lung specific overexpression of the bioactive form
of the human TGFβ1 gene and by repetitive administration of low-dose inhaled bleomycin. While exciting,
however, these studies are limited by not having determined whether mtDNA-induced fibroblast activation
requires TLR9, whether TLR9’s fibrosis promoting effects are mediated through fibroblasts in vivo, and the nature
of the mtDNA-TLR9 relationship in IPF. Because elucidation of these questions might substantially impact our
understanding of pulmonary fibrosis, t...

## Key facts

- **NIH application ID:** 10457967
- **Project number:** 5K08HL151970-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Changwan Ryu
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $167,940
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457967

## Citation

> US National Institutes of Health, RePORTER application 10457967, Mitochondrial DNA and TLR9 in Pulmonary Fibrosis (5K08HL151970-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457967. Licensed CC0.

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