Model of chemotherapy-induced mucositis

化疗引起的粘膜炎模型

基本信息

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
项目类别：
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

项目摘要

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）：口服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足够疼痛，因此可能需要减少剂量和/或推迟抗塑性治疗。尽管这些病变具有临床意义，但其发病机理涉及的特定细胞事件目前缺乏了解分子靶向疗法或预防策略的知识不足。对高度增殖的基础上皮细胞的细胞毒性是关键因素帽子引发了消化道粘膜的组织损伤。但是，越来越清楚的是，炎症性级联反应和微生物营养不良的激活也可能在病变的发育或进展中起主要作用。文献中缺乏关于微生物在粘膜炎开始或进展中的作用的共识，因为相关的多因素菌落定殖的实验模型不存在。我们建议使用我们已建立的口服和食管粘膜的三维系统，这些系统融合了唾液和营养流，以开发新型的体外粘膜损伤模型，以模仿化学疗法诱导的人类粘膜炎。这些模型将提供一个与生物学相关的框架，可以在细胞和分子水平上解剖化学疗法药物的作用机理，以及在损伤开发或解决过程中可以“实时”检查局部微生物菌群的效果。所提出的模型的新颖性和意义在于，它们提供了一种组织复杂性，该组织复杂性是单细胞类型和人体器官培养物之间的，并整合唾液/养分流量并暴露于共生微生物联盟，从而繁殖了人类口腔环境的条件。这种体外模型在这种情况的病理生物学中的应用是新颖的，并且可能改变范式。在第一个目标中，我们将建立临床上相关的药理学诱导的粘膜损伤模型，表征口腔和食管细胞的凋亡和促炎反应，并使用口服粘膜炎的小鼠模型来验证这些反应。在第二个目标中，使用口服和食管的体外模型以及小鼠口服粘膜炎模型，我们将表明化学疗法诱导的粘膜改变允许对可导致炎症和组织损伤的共生细菌和真菌种类的优先定殖。这项工作将为设计新型抗菌和伤口愈合的设计奠定基础，从而促进控制上消化道及其相关多性多细胞感染的粘膜炎病变。 1