Mast Cells and innate immunity in otitis media

肥大细胞和中耳炎的先天免疫

• 批准号: 7082158
• 负责人: Stephen I Wasserman
• 金额: $ 29.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082158
• 关键词: Haemophilus influenzae; RNase protection assay; allergens; apoptosis; bacteria infection mechanism; bacterial proteins; cell adhesion; cell migration; cell proliferation; disease /disorder model; histamine; host organism interaction; immunity; immunization; immunocytochemistry; laboratory mouse; leukocytes; leukotrienes; mast cell; middle ear; neutrophil; otitis media; polymerase chain reaction; toll like receptor; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Otitis media is a major health problem causing substantial morbidity and resulting in substantial health care expenditures. The causes and treatment of this disorder remain incompletely understood. Eustachian tube obstruction, viral and subsequent bacterial infection and immunity have each been suggested to contribute to the etiopathophysiology of this disorder. Recent work in our laboratories has indicated that concurrent mast cell activation and bacterial infection can synergistically interact to induce strong inflammatory changes in the middle ear. These preliminary data, as well as prior research in the middle ear and other systems, suggest that the mast cell may play an important role in the innate and cognate defense of the middle ear, and may also contribute to otitis media pathogenesis. In this proposal Drs. S. Wasserman, A. Ryan and D. Broide propose a series of integrated experiments employing genetically modified mice to validate this hypothesis and to elucidate the mechanism(s) by which this synergistic interaction occurs. Aim 1 of this proposal will define the synergistic interaction utilizing mast cell deficient mice, with and without, reconstitution of their middle ear mast cells. Aim 2 will examine the mechanisms by which bacterial products enhance mast cell mediated synergistic inflammation by exploring the Toll-like receptor (TLR) pathways of mast cells. In these experiments TLR 2, 4, and 9 deficient mast cells will be used to re-constitute middle ear mast cell populations of mast cell deficient mice and the effect of bacterial/ mast cell interactions defined. MyD88 deficient mice, defective in all TLR signaling will be used to define potential redundancies in these responses. Aim 3 will re-constitute middle ear mast cells with mast cell populations obtained from mice which are deficient in one or more mast cell mediators including histamine, leukotriene and tumor necrosis factor alpha to define the mediator(s) responsible for mast cell enhancement of inflammation induced in the presence of bacteria. Aim 4 will elucidate the leukocyte/endothelial mechanisms by which mast cell] bacterial interactions enhance inflammation, by direct observations of leukocyte behavior in genetically modified animals. Together these studies will expand our understanding of the role of mast cells in otitis media and may identify new targets for therapeutic intervention.

描述（由申请人提供）：中耳炎是导致大量发病率和大量医疗支出的主要健康问题。这种疾病的病因和治疗方法仍不完全清楚。耳咽管阻塞，病毒和随后的细菌感染和免疫都被认为是导致这种疾病的病因生理学。我们实验室最近的工作表明，肥大细胞激活和细菌感染可以协同相互作用，诱导中耳强烈的炎症变化。这些初步数据以及先前对中耳和其他系统的研究表明，肥大细胞可能在中耳的先天和同源防御中发挥重要作用，并可能参与中耳炎的发病机制。在这个提案中，博士。s. Wasserman, a . Ryan和D. Broide提出了一系列采用转基因小鼠的综合实验来验证这一假设，并阐明这种协同作用发生的机制。本提案的目的1将定义利用肥大细胞缺陷小鼠的协同相互作用，无论是否重组其中耳肥大细胞。目的2将通过探索肥大细胞的toll样受体（TLR）途径来研究细菌产物增强肥大细胞介导的协同炎症的机制。在这些实验中，tlr2、4和9缺陷肥大细胞将被用来重建肥大细胞缺陷小鼠的中耳肥大细胞群，并确定细菌/肥大细胞相互作用的影响。MyD88缺陷小鼠，所有TLR信号都有缺陷，将用于定义这些反应中的潜在冗余。目的3将用从缺乏一种或多种肥大细胞介质（包括组胺、白三烯和肿瘤坏死因子α）的小鼠中获得的肥大细胞群重建中耳肥大细胞，以确定在细菌存在下肥大细胞增强炎症的介质。目的4将通过直接观察转基因动物的白细胞行为，阐明肥大细胞细菌相互作用增强炎症的白细胞/内皮机制。总之，这些研究将扩大我们对肥大细胞在中耳炎中的作用的理解，并可能确定治疗干预的新靶点。