Model of chemotherapy-induced mucositis

化疗引起的粘膜炎模型

• 批准号: 8770223
• 负责人: Anna I Dongari-Bagtzoglou
• 金额: $ 22.97万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770223
• 关键词: Adverse effects; Apoptotic; Area; Blood; Cancer Patient; Cells; Chemotherapy-Oncologic Procedure; Clinical; Complex; Consensus; Development; Dose; Environment; Epithelial; Epithelial Cells; Erythema; Esophageal; Esophageal mucous membrane; Esophagitis; Event; Experimental Models; Exposure to; Fatal Outcome; Foundations; Gastrointestinal tract structure; Goals; Growth; Human; Immunocompromised Host; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Length of Stay; Lesion; Literature; Lower Gastrointestinal Tract; Malignant Neoplasms; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Nutrient; Oral; Oral mucous membrane structure; Organ Culture Techniques; Organism; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Prevention strategy; Preventive; Process; Public Health; Quality of Care; Quality of life; Rattus; Regimen; Research; Resolution; Role; Salivary; Speech; Stream; Streptococcus; Surface; Surveys; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Ulcer; Work; Wound Healing; antimicrobial; bench to bedside; cancer care; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; clinically relevant; clinically significant; cytotoxicity; design; effective therapy; improved; in vitro Model; in vivo; injured; meetings; microbial; microbial colonization; microbiome; microorganism; monolayer; mouse model; neoplastic; news; novel; nutrition; oral commensal; oral condition; oral microbiome; oral mucositis; pathogen; public health relevance; response; symposium; tool

DESCRIPTION (provided by applicant): Oral and esophageal mucositis are common side effects of cancer chemotherapy. Severe oral mucositis can be sufficiently painful so that dose reductions and/or postponement of anti-neoplastic treatments may be necessary. Despite the clinical significance of these lesions, the specific cellular events involved in their pathogenesis are poorly understood and thus molecularly-targeted therapies or prevention strategies are currently lacking. Cytotoxicity to the highly proliferative basal epithelial cells is a key factor hat initiates tissue injury in the alimentary tract mucosa; however, it is becoming increasingly clear that activation of inflammatory cascades and microbial dysbiosis may also play major roles in the development or progression of the lesions. There is lack of consensus in the literature regarding the role of microorganisms in the initiation or progression of mucositis since relevant experimental models of polymicrobial colonization of are non-existent. We propose to use our established three-dimensional systems of the oral and esophageal mucosa which incorporate salivary and nutrient flow, to develop novel in vitro mucosal injury models that mimic chemotherapy-induced mucositis in humans. These models will provide a biologically relevant framework where mechanisms of action of chemotherapy medications can be dissected at the cellular and molecular levels and where the effect of the local microbial flora can be examined "in real time" during development or resolution of the injury. The novelty and significance of the proposed models is that they provide an organizational complexity that is between the culture of single cell types and human organ cultures, and integrate salivary/nutrient flow and exposure to commensal microbial consortia, which reproduce conditions of the oral environment in humans. The application of such in vitro models in the pathobiology of this condition is novel and potentially paradigm shifting. In the first aim we will establish a clinically relevant pharmacologically-induced in vitro model of mucosal injury, characterize the apoptotic and proinflammatory responses of oral and esophageal cells and validate these using a mouse model of oral mucositis. Using the oral and esophageal in vitro models as well as a mouse oral mucositis model in the second aim we will show that chemotherapy-induced mucosal alterations allow preferential colonization of commensal bacterial and fungal species that can contribute to inflammation and tissue damage. This work will lay the foundation for the design of novel combined antimicrobial and wound healing promoting strategies to control mucositis lesions of the upper alimentary tract and their associated polymicrobial infections. 1

描述（由申请人提供）：口腔和食管粘膜炎是癌症化疗的常见副作用。严重的口腔粘膜炎可能非常疼痛，因此可能需要减少剂量和/或推迟抗肿瘤治疗。尽管这些病变具有临床意义，但其发病机制中涉及的特定细胞事件 对这些疾病的了解很少，因此目前缺乏分子靶向治疗或预防策略。对高度增殖的基底上皮细胞的细胞毒性是引发消化道粘膜组织损伤的关键因素;然而，越来越清楚的是，炎症级联反应和微生物生态失调的激活也可能在病变的发展或进展中起主要作用。关于微生物在粘膜炎的起始或进展中的作用，文献中缺乏共识，因为不存在多微生物定植的相关实验模型。我们建议使用我们建立的口腔和食管粘膜的三维系统，其中包括唾液和营养流，开发新的体外粘膜损伤模型，模仿化疗诱导的人类粘膜炎。这些模型将提供一个生物学相关的框架，其中可以在细胞和分子水平上剖析化疗药物的作用机制，并且可以在损伤的发展或消退期间“在真实的时间”检查局部微生物植物群的影响。所提出的模型的新奇和重要性在于，它们提供了介于单细胞类型的培养物和人体器官培养物之间的组织复杂性，并整合了唾液/营养流和暴露于口腔微生物聚生体，其再现了人类口腔环境的条件。这种体外模型在这种疾病的病理生物学中的应用是新颖的，并且可能是范式转变。在第一个目标中，我们将建立一个临床相关的药理学诱导的粘膜损伤的体外模型，表征口腔和食管细胞的凋亡和促炎反应，并使用小鼠口腔粘膜炎模型验证这些。在第二个目标中，使用口腔和食管体外模型以及小鼠口腔粘膜炎模型，我们将表明化疗诱导的粘膜改变允许可能导致炎症和组织损伤的肠道细菌和真菌物种的优先定植。这项工作将奠定基础的设计新的组合抗菌和伤口愈合促进战略，以控制上消化道粘膜炎病变及其相关的多微生物感染。1