Immunopathogenesis of Adenovirus Keratitis

腺病毒角膜炎的免疫发病机制

基本信息

批准号：
7490426
负责人：
James Chodosh
金额：
$ 44.79万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7490426
关键词：
Acute Address Adenovirus Infections Adenoviruses Binding Binding Sites Biological Assay Blindness Capsid Caring Cells Cellular biology Characteristics Chemicals Chemotactic Factors Clinical Conjunctivitis Cornea Corneal Diseases Corneal Stroma Development Dominant-Negative Mutation Enzyme-Linked Immunosorbent Assay Epidemic Epidemic Keratoconjunctivitis Epithelial Experimental Designs Extracellular Matrix Eye Eye Infections Fibroblasts Figs - dietary Foreign Bodies Future Gases Gene Expression Goals Health Human Hypesthesia Immune response Immunology Immunoprecipitation In Vitro Infection Infiltration Inflammation Integrins Interleukin-8 Intervention Keratitis Laboratories Leukocytes MAPK11 gene MAPK8 gene Mediating Mediator of activation protein Microinjections Mitogen-Activated Protein Kinases Mitogens Modeling Molecular Monocyte Chemoattractant Protein-1 Mus Natural Immunity Patients Phosphotransferases Photophobia Process Proteins Pseudomembranous Conjunctivitis RNA Regulation Reporter Research Personnel SRC gene Serotyping Signal Transduction Signaling Molecule Specificity Subgroup System Testing Time Transfection Viral Virus Vision research Visual impairment Western Blotting Work base chemokine corneal epithelium inhibitor/antagonist innovation migration mouse model mutant novel pathogen prevent programs response therapeutic target transcription factor virology

项目摘要

DESCRIPTION (provided by applicant): Ocular infection by subgroup D adenovirus (Ad) serotypes 8, 19, and 37 causes epidemic kerato-conjunctivitis (EKC), manifested by acute pseudomembranous conjunctivitis, punctate and macro-epithelial erosions, and delayed onset stromal keratitis. In EKC, the delayed infiltration of leukocytes into the subepithelial corneal stroma causes light sensitivity, foreign body sensation, and reduced vision, sometimes lasting for months to years after infection. Our goal is to dissect the molecular mechanisms for the development of stromal keratitis in EKC, which at this time remain obscure. We hypothesize that adenoviral subepithelial infiltrates result when infection of superficial keratocytes induces a specific intracellular signal transduction cascade, leading to expression of proinflammatory mediators into the corneal stroma, that in turn cause leukocyte migration into the corneal extracellular matrix. We propose three specific aims: 1) to test the hypothesis that c-Src acts as a global regulator of intracellular signaling and chemokine gene expression in adenovirus-infected corneal fibroblasts, 2) to test the hypothesis that mitogen-activated protein kinases determine the specificity of chemokine gene expression after adenovirus infection of corneal fibroblasts, and 3) to test the hypothesis that inhibitors of intracellular signaling will reduce inflammation in the mouse adenovirus keratitis model. Our experimental design will utilize both cultured human corneal fibroblasts and a new mouse model of adenovirus keratitis, in which characteristic and reproducible leukocyte infiltration follows Ad inoculation. Interventions will include use of chemical inhibitors of cell signaling, dominant negative and constitutively active kinases, and short interfering RNA against chemokine transcription factors. Our long-term objective is to understand the interplay between adenoviruses and immune responses in the human cornea, so that information-based therapies against adenovirus keratitis can be developed. Adenoviruses represent perhaps the most common ocular pathogen in the industrialized world. The overall health relevance of these studies derives from our discovery and elucidation of novel mechanisms of innate immune responses in the cornea that cause keratitis in EKC.

描述（申请人提供）：D亚型腺病毒（Ad）血清型8、19和37的眼部感染引起流行性角结膜炎（EKC），表现为急性假膜性结膜炎、点状和大上皮糜烂以及迟发性基质角膜炎。在 EKC 中，白细胞延迟浸润到上皮下角膜基质会导致光敏感、异物感和视力下降，有时在感染后持续数月至数年。我们的目标是剖析 EKC 基质性角膜炎发生的分子机制，目前该机制仍不清楚。我们假设，当浅层角膜细胞感染诱导特定的细胞内信号转导级联，导致促炎介质表达到角膜基质中时，导致腺病毒上皮下浸润，进而导致白细胞迁移到角膜细胞外基质中。我们提出了三个具体目标：1) 检验 c-Src 在腺病毒感染的角膜成纤维细胞中作为细胞内信号传导和趋化因子基因表达的全局调节剂的假设，2) 检验丝裂原激活蛋白激酶决定特异性的假设腺病毒感染角膜成纤维细胞后趋化因子基因表达的变化，以及3）检验细胞内信号传导抑制剂将减少小鼠腺病毒炎症的假设角膜炎模型。我们的实验设计将利用培养的人角膜成纤维细胞和新的腺病毒角膜炎小鼠模型，其中在接种Ad后出现特征性且可重复的白细胞浸润。干预措施包括使用细胞信号传导的化学抑制剂、显性失活和组成型活性激酶以及针对趋化因子转录因子的短干扰RNA。我们的长期目标是了解腺病毒与人类角膜免疫反应之间的相互作用，以便开发针对腺病毒角膜炎的基于信息的疗法。腺病毒可能是工业化世界中最常见的眼部病原体。这些研究的整体健康相关性源于我们对角膜先天免疫反应新机制的发现和阐明，该机制导致 EKC 角膜炎。