# Methylation signaling in periodontal health and disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $391,875

## Abstract

PROJECT SUMMARY ABSTRACT
Periodontitis is the second most prevalent infectious disease of mankind. It is a chronic inflammatory condition
that leads to the destruction of tooth-supporting structures, including the gingiva, periodontal ligament and
alveolar bone. It is the main cause of tooth loss and induces systemic implications, including cardiovascular
disorders, preterm birth and cancer. While a microbial biofilm is the main cause of periodontitis, it is
increasingly recognized that the host inflammatory responses determine the outcome of periodontal disease.
Therefore elucidation the molecular signaling network controlling inflammatory responses is crucial for
understanding and treating this disease. Dysregulation of signaling networks that serve to control inflammation
is often causative for periodontitis. Toll-like receptor (TLR) signaling is the master pro-inflammatory pathway,
while transforming growth factor β (TGFβ) signaling is a major anti-inflammation pathway. Balance between
pro- and anti-inflammation signaling networks of TLR and TGFβ defines the immune responses. In sepsis and
vascular inflammation, TGFβ-elicited inhibition of TLR signaling occurs through the induction of inhibitory
Smad6. In periodontal tissues, we found that Smad6 is highly expressed in gingival epithelium and disturbance
of Smad6 activity exacerbated periodontal bone loss, suggesting that TGFβ-elicited inhibition of TLR signaling
may regulate periodontitis through controlling gingival epithelial signaling network. We investigated
mechanisms of Smad6 action in gingival epithelial cells and identified a novel step in signaling cascades for
TLR inhibition that involves Smad6 methylation. We hypothesize that Smad6 methylation suppresses
inflammation in gingival epithelium to maintain homeostasis and ameliorate periodontitis through switching on
TGFβ-elicited inhibition of TLR signaling. We propose to use mouse genetic models (Aim 1 and 2) to
investigate roles of Smad6 methylation in periodontal homeostasis and disease, and cell and biochemical
approaches (Aim 3) to understand the molecular regulatory mechanisms of periodontal inflammatory
responses. This novel mechanism involving Smad6 methylation is a previously unknown step in TLR signaling
regulation and introduces new point of intervention with therapeutic potential.

## Key facts

- **NIH application ID:** 10179356
- **Project number:** 5R01DE026468-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jian Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $391,875
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179356

## Citation

> US National Institutes of Health, RePORTER application 10179356, Methylation signaling in periodontal health and disease (5R01DE026468-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179356. Licensed CC0.

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