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

• 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
• 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

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.

项目摘要 口腔粘膜炎是癌症化学疗法最常见的合并症之一。由于其症状和 相关并发症，口腔粘膜炎会影响最佳癌症治疗的递送。口服粘膜炎 首先是化学疗法对快速分裂口服上皮的细胞毒性作用的结果。然而， 粘膜损伤所涉及的特定细胞事件尚未完全理解，从而阻碍了 开发有效的治疗方法。细胞死亡和炎症是粘膜炎的标志。虽然DNA 损伤和凋亡已被认为是导致口服粘膜炎的主要机制 细胞死亡触发宿主衍生的损伤相关分子模式（潮湿）和激活的释放 居民微生物分子的炎症反应也可能涉及。初步观察 在5-FU诱导的口腔粘膜炎的小鼠模型中，表明碱性上皮细胞的凋亡是一种早期反应， 但是细胞死亡的非凋亡形式可能介导晚期组织损伤。因此有必要评估 在化学疗法引起的口服期间激活的细胞死亡途径和介质的暂时进展 粘膜炎。在这里，我们将探讨凋亡介导早期反应的假设，而非凋亡 通过感测湿或不植物微生物组的感知，细胞死亡和炎症激活形式有助于 组织损伤的最新阶段。我们将专门专注于评估促凋亡介质PMAIP1的作用， 在化学疗法期间，在人口腔粘膜中发现了这种情况。我们还将测试是否发出信号 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。水平 TNF-α在口服粘膜炎期间增加，并与其严重程度有关。感官潮湿的TLR4是 在口腔粘膜中表达，已被证明可以介导较低的胃肠道粘膜炎，但在 尚未评估口腔粘膜炎。此外，口服粘膜炎与微生物组营养不良有关，与 病原体的富集，这可能有助于扩大TLR依赖或独立的组织损伤 方式。根据该建议，我们将使用5-FU诱导的口服粘膜炎的小鼠模型来识别 组织损伤的介体。在AIM 1中，我们将纵向表征导致细胞死亡和的途径 5-FU诱导的粘膜炎期间的炎症损伤，并通过敲除菌株和机械评估 药理学抑制剂PMAIP1，TNF-α和TLR4作为病理生理介质的贡献。在 AIM 2我们将表征在5-FU-期间口腔微生物组和微生物组织侵袭中的不植物变化 诱导口服粘膜炎。然后，我们将测试抗生素方案的作用，显示为有选择或完全复制 口服共生，在粘膜炎过程中，将评估失调群落的转移是否会调节 口腔粘膜炎的严重程度。我们设想这些研究将指出关键的组织损伤介质和上皮微粒 调节粘膜炎病理生理学并指导疗法发展的相互作用。