# Mechanisms of Cell Death and Inflammation in Chemotherapy-Induced Oral Mucositis

> **NIH NIH R56** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $656,885

## Abstract

Project summary
Oral mucositis is one of the most common comorbidities of cancer chemotherapy. Due to its symptoms and
associated complications, oral mucositis can impact the delivery of optimal cancer treatment. Oral mucositis
primarily results from the cytotoxic effect of chemotherapeutics on the rapidly dividing oral epithelium. However,
the specific cellular events involved in mucosal injury remain incompletely understood, thereby hampering the
development of effective treatments. Cell death and inflammation are hallmarks of mucositis. Although DNA
damage and apoptosis have been considered the main mechanisms that lead to oral mucositis, lytic forms of
cell death triggering the release of host-derived damage-associated molecular patterns (DAMPS) and activation
of inflammatory responses by resident microbial commensals could also be involved. Preliminary observations
in a mouse model of 5-FU-induced oral mucositis suggest apoptosis of basal epithelial cells is an early response,
but non-apoptotic forms of cell death are likely to mediate late tissue injury. There is therefore a need to evaluate
the temporal progression of cell death pathways and mediators activated during chemotherapy-induced oral
mucositis. Here we will explore the hypothesis that apoptosis mediates early responses, while non-apoptotic
forms of cell death and activation of inflammation by sensing of DAMPs or a dysbiotic microbiome contribute to
late stages of tissue injury. We will specifically focus on evaluating the role of the pro-apoptotic mediator PMAIP1,
which was found as upregulated in human oral mucosa during chemotherapy. We will also test if signaling
through tumor necrosis factor (TNF)-α and/or Toll-like receptor 4 (TLR4) leads to oral mucosal injury. Levels of
TNF-α increase during oral mucositis and are associated with its severity. TLR4, which senses DAMPs, is
expressed in the oral mucosa and has been shown to mediate lower gastrointestinal mucositis, but its role in
oral mucositis has not been evaluated. Furthermore, oral mucositis is associated with microbiome dysbiosis, with
an enrichment of pathobionts, which could contribute to amplify tissue injury in a TLR-dependent or independent
manner. Accordingly, in this proposal we will use our mouse model of 5-FU-induced oral mucositis to identify
mediators of tissue injury. In Aim 1, we will longitudinally characterize pathways leading to cell death and
inflammatory damage during 5-FU-induced mucositis and mechanistically evaluate via knockout strains and
pharmacological inhibitors the contribution of PMAIP1, TNF-α and TLR4 as mediators of pathophysiology. In
Aim 2 we will characterize dysbiotic changes in the oral microbiome and microbial tissue invasion during 5-FU-
induced oral mucositis. We will then test the effect of antibiotic regimens, shown to selectively or totally deplete
oral commensals, on the course of mucositis and will evaluate if transfer of a dysbiotic community modulates
oral mucositis severity...

## Key facts

- **NIH application ID:** 10251626
- **Project number:** 1R56DE028545-01A1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Patricia Diaz
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $656,885
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251626

## Citation

> US National Institutes of Health, RePORTER application 10251626, Mechanisms of Cell Death and Inflammation in Chemotherapy-Induced Oral Mucositis (1R56DE028545-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10251626. Licensed CC0.

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