# Small molecule mediated restoration of periodontal homeostasis through the YAP1 pathway

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2020 · $352,958

## Abstract

Abstract
 Regeneration of periodontal tissues including formation of new alveolar bone, and
generation of new connective tissue attachment have been the ultimate goals of periodontal
research and therapy since the 1980ies. Here we have identified the highly selective SETD7
methyltransferase activity inhibitor (R)-PFI-2 (PFI-2) as a powerful small molecule modulator that
ameliorated the severity of periodontal inflammation and significantly promoted new alveolar bone
formation, new cementum formation, and periodontal ligament re-attachment. When PFI-2 was
applied to periodontal defects in our rodent model, there was a substantial 1.7-fold increase in
alveolar bone height equivalent to a 3 mm gain in vertical bone of attachment levels in humans
when compared to controls. These preliminary data indicate that PFI-2 might represent a new
answer to the quest for periodontal regeneration and a molecule capable of tipping the periodontal
homeostasis balance in favor of the anabolic side. Explaining the mechanisms by which PFI-2
affects periodontal stem cell function, our preliminary data have demonstrated that PFI-2 treatment
increased YAP1 nuclear translocation and downstream gene expression, suggesting that PFI-2
affects periodontal gene expression under inflammatory conditions through a novel pathway that
includes the methyltransferase SETD7 and the Hippo pathway member YAP1. Based on these
exciting preliminary data we have now hypothesized that PFI-2 upregulates YAP1 target gene
expression through nuclear translocation, resulting in improved periodontal progenitor proliferation
and differentiation, and reduced periodontal bone loss under inflammatory conditions. We
anticipate that these studies will result in the development of novel small molecule-based
therapeutics for the treatment of periodontal disease and to combat the associated loss of
periodontal tissue that will aid the practicing periodontist.

## Key facts

- **NIH application ID:** 9892878
- **Project number:** 5R01DE026198-04
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Tom Diekwisch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,958
- **Award type:** 5
- **Project period:** 2017-04-19 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892878

## Citation

> US National Institutes of Health, RePORTER application 9892878, Small molecule mediated restoration of periodontal homeostasis through the YAP1 pathway (5R01DE026198-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9892878. Licensed CC0.

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