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

化疗引起的口腔粘膜炎细胞死亡和炎症的机制

基本信息

批准号：
10251626
负责人：
Patricia Diaz
金额：
$ 65.69万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251626
关键词：
Address Alpha Cell Amplifiers Anaerobic Bacteria Animal Model Animals Antibiotics Antineoplastic Agents Apoptosis Apoptotic Appearance Cell Cycle Kinetics Cell Death Chemotherapy-Oncologic Procedure Clinical Communities DNA Damage Data Development Disease Dose E-Cadherin Epithelial Epithelial Cells Epithelium Erythema Evaluation Event Fluorouracil Functional disorder Gene Expression Profiling Homeostasis Hospitalization Human In Vitro Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 beta Knock-out Knockout Mice Knowledge Lead Lesion Lytic Malignant Neoplasms Mediating Mediator of activation protein Microbe Microbiology Modeling Molecular Mucositis Mucous Membrane Nuclear Oral Oral Stage Oral mucous membrane structure Outcome PMAIP1 gene Pain Pathway interactions Pattern Pharmacology Proteins Regimen Role Salivary Sepsis Series Severities Signal Transduction Symptoms TLR4 gene TNF gene Testing Tissues Toll-like receptors Treatment outcome Ulcer Up-Regulation Work cancer complication cancer therapy chemotherapy comorbidity cytokine cytotoxic dysbiosis effective therapy experimental study gastrointestinal human model in vitro Model inhibitor/antagonist intestinal epithelium microbial microbiome mouse model novel strategies nutrition oral cavity epithelium oral commensal oral microbiome oral mucositis pathobiont response sensor targeted treatment therapy development tissue injury transcriptome

项目摘要

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. We envision these studies will point to key tissue injury mediators and epithelial-microbe interactions that modulate mucositis pathophysiology and will guide the development of therapies.

项目总结