# Endogenous Regulators of Inflammation in Periodontal Tissue Homeostasis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $382,078

## Abstract

Strategy of targeting endogenous regulators has emerged to limit inflammation and preserve tissue
homeostasis opening a new paradigm in the treatment of chronic infectious and inflammatory conditions
including periodontal disease. Ubiquitination is a reversible post-translational modification that can terminate
cell signaling through proteasome-mediated degradation and also involved in protein trafficking and activation
of kinases and phosphatases thereby playing a key role in the regulation of multiple inflammatory signaling
cascades. While ubiquitination is essential to activate immune responses, its tight regulation and timely
termination is the key to keep the potentially damaging inflammatory signals in check and preserve tissue
homeostasis. Therefore, ubiquitination and ubiquitin-related events are essential in the regulation of functional
immune cell plasticity and homeostatic events. However, there are yet no studies which investigated their role
on the oral mucosa. Recently, A20 (also known as TNF alpha induced protein 3 or TNFAip3) has emerged as
a critical negative regulator of inflammation through interfering with ubiquitination. A20 lies downstream of Toll
like receptors (TLRs), NOD-like receptors, T cell receptor, and cytokine receptors (e.g. TNFR, IL-1R, IL-17R)
and regulates inflammation mainly by restricting NF-κB pathway and modulates other cellular functions such as
apoptosis, necroptosis and autophagy. Through its function in a diverse set of biological mechanisms, A20 is
implicated in gastrointestinal, cardiovascular, and pulmonary diseases, autoimmune and neurological
disorders, rheumatoid arthritis, aging and mostly in cancer. Likewise, we now have evidence supporting the
hypothesis that A20 is one of the key regulatory factors within the oral mucosa and acts as a gatekeeper to
restrict periodontal inflammation through interfering with critical upstream and downstream events. The overall
goal of the current proposal is to delineate the role of ubiquitination with specific focus being on the function
and regulation of A20 in host-oral microbiome interactions as they relate to the key cellular and molecular
pathways in the course of periodontitis. We seek to uncover a previously unexplored area within the oral cavity
through conducting complementary experiments involving clinical studies and well characterized preclinical
disease models. The proposed studies are expected to unveil novel biological and mechanistic insights and
lead to new concepts and therapeutics not only for periodontal disease but also for other local infection driven
inflammatory conditions as well as diseases associated with PD such as oral cavity malignancies and aging
related conditions.

## Key facts

- **NIH application ID:** 10407028
- **Project number:** 5R01DE027374-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sinem Esra Sahingur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,078
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407028

## Citation

> US National Institutes of Health, RePORTER application 10407028, Endogenous Regulators of Inflammation in Periodontal Tissue Homeostasis (5R01DE027374-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407028. Licensed CC0.

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