# TLR4-MEDIATED EPIGENETIC AND SENESCENCE MECHANISMS IN EMPHYSEMA

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $291,319

## Abstract

PROJECT SUMMARY
COPD is now the 3rd leading cause of death worldwide. Emphysema, characterized by airspace enlargement
and impaired gas exchange, is a major subtype of COPD. The cumulative effects of cigarette smoke exposure
(CS) and environmental toxins across the lifespan are important contributing factors to the development of
emphysema. Yet very little is known about the underlying mechanisms, which limits therapies. Our overall
goals are to understand the molecular mechanisms of how our lungs maintain normal structural integrity and
how they protect against inhaled toxins, such as CS. We identified a critical role for an innate immune receptor,
Toll-like receptor 4 (TLR4), in lung maintenance and in preventing inappropriate activation of aging and injury
pathways. Unfortunately, age and CS, two of the most common risk factors for COPD, result in inadequate
levels of TLR4, thus predisposing to emphysema. Our studies will fill current gaps in our understanding of how
the immune system, in specific lung cells, can impact lung-protective responses even in the absence of
infection, thereby offering potential new therapeutic targets. Using TLR4-deficiency and CS as clinically
relevant experimental models of emphysema, we identified mechanistic roles for the senescence molecule,
p16INK4A, and DNA-modifying enzymes, HDAC2, Dnmt3a and Tet2, in emphysema. In addition, we offer the
first in vivo evidence that increased p16INK4A contributes to emphysema. Our overall hypothesis is that
structural cell TLR4 is required to maintain normal lung integrity, at baseline and after CS, by inhibiting
p16INK4A via HDAC2-Dnmt3a-Tet2-mediated mechanisms. We will use a combination of age- and CS-
exposed human and mouse lungs/cells as well as innovative gene manipulations to test this hypothesis in the
following Aims: 1) Identify mechanisms of decreased TLR4 expression with aging and CS and the
contribution of TLR4 in specific structural cells to emphysema. 2) Determine the mechanisms of decreased
HDAC2 in TLR4-deficient and CS-exposed cells. 3) Identify HDAC2 and Dnmt3a / Tet2 -mediated mechanisms
of p16INK4A induction and the contribution of p16INK4A in specific structural cells to emphysema. Our studies will
expand our basic understanding of the molecular drivers of emphysema, establish previously unrecognized
interactions amongst innate immunity, senescence and DNA modifications and inform future preventative or
therapeutic approaches to a range of age- and CS-related lung diseases.

## Key facts

- **NIH application ID:** 10013285
- **Project number:** 5R01HL138396-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** PATTY J LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $291,319
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013285

## Citation

> US National Institutes of Health, RePORTER application 10013285, TLR4-MEDIATED EPIGENETIC AND SENESCENCE MECHANISMS IN EMPHYSEMA (5R01HL138396-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10013285. Licensed CC0.

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