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.

项目概要由于其症状和特点，口腔粘膜炎是癌症化疗最常见的合并症之一。相关并发症、口腔粘膜炎可能会影响最佳癌症治疗的实施。主要是由于化疗药物对快速分裂的口腔上皮的细胞毒性作用所致。与粘膜损伤有关的特定细胞事件仍不完全清楚，从而阻碍了细胞死亡和炎症是粘膜炎的标志。细胞凋亡被认为是导致口腔粘膜炎、溶解形式的口腔粘膜炎的主要损伤机制。细胞死亡触发宿主源性损伤相关分子模式 (DAMPS) 的释放和激活初步观察也可能涉及常驻微生物共生体的炎症反应。在 5-FU 诱导的口腔粘膜炎小鼠模型中，表明基底上皮细胞凋亡是一种早期反应，但非凋亡形式的细胞死亡可能会介导晚期组织损伤，因此需要进行评估。化疗诱导口服期间细胞死亡途径和介质激活的时间进展在这里，我们将探讨细胞凋亡介导早期反应的假设，而非细胞凋亡。通过感知 DAMP 或失调的微生物群而导致细胞死亡和炎症激活的形式我们将特别关注评估促凋亡介质 PMAIP1 的作用，我们还将测试其是否在化疗期间在人类口腔粘膜中表达上调。通过肿瘤坏死因子（TNF）-α和/或Toll样受体4（TLR4）导致口腔粘膜损伤。口腔粘膜炎期间 TNF-α 增加，并且与感知 DAMP 的 TLR4 的严重程度相关。在口腔粘膜中表达，并已被证明可介导下消化道粘膜炎，但其作用此外，口腔粘膜炎与微生物群失调有关。丰富的致病生物，可能有助于放大 TLR 依赖或独立的组织损伤因此，在本提案中，我们将使用 5-FU 诱导的口腔粘膜炎小鼠模型来识别。在目标 1 中，我们将纵向描述导致细胞死亡和损伤的途径。 5-FU 诱导的粘膜炎期间的炎症损伤，并通过敲除菌株进行机械评估药理学抑制剂 PMAIP1、TNF-α 和 TLR4 作为病理生理学介质的贡献。目标 2 我们将描述 5-FU- 期间口腔微生物群和微生物组织入侵的生态失调变化。然后我们将测试抗生素治疗方案的效果，显示其可以选择性或完全耗尽抗生素。口腔共生体，关于粘膜炎的病程，并将评估菌群失调的转移是否会调节我们预计这些研究将指出关键的组织损伤介质和上皮微生物。调节粘膜炎病理生理学的相互作用并将指导治疗的开发。