Immunopathogenesis of Adenovirus Keratitis

腺病毒角膜炎的免疫发病机制

基本信息

批准号：
7811257
负责人：
James Chodosh
金额：
$ 135.04万
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：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-03-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7811257
关键词：
Acute Address Adenovirus Infections Adenoviruses Basic Science Bioinformatics Biology Child Code Collaborations Complementarity Determining Regions Cornea Corneal Diseases Corneal Stroma Data Development Disease Outbreaks Epidemic Keratoconjunctivitis Epithelial Event Evolution Experimental Designs Eye Infections Fibroblasts Figs - dietary Funding Gene Expression Genetic Recombination Genitourinary System Infection Genome Genomics Genotype Germany Goals Grant Health Human Human Adenoviruses Immune Immune response Immunity Individual Infection Infiltration Inflammation Japan Keratitis Lead Leukocytes Light Military Personnel Mitogen-Activated Protein Kinases Modeling Molecular Mus Open Reading Frames Parents Pathogenesis Pattern Philanthropic Fund Population Proteins Pseudomembranous Conjunctivitis Ramp Recovery Recruitment Activity Recurrence Research Research Personnel Risk Role SRC gene Satellite Viruses Scientist Sequence Analysis Signal Transduction Software Tools Solid Specificity Stromal Cells Subgroup Surveys Syndrome TPD52L1 gene Testing Time Tropism United States National Institutes of Health Viral Virus Visual impairment Work base career chemokine depressed gastrointestinal genome sequencing inhibitor/antagonist interest novel pathogen penton base public health relevance respiratory success tissue tropism wasting

项目摘要

DESCRIPTION (provided by applicant): This application is submitted under NOT-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Ocular infection by human adenovirus (HAdV) species D genotypes D8, D19, D37, and D53 causes epidemic keratoconjunctivitis (EKC), manifest 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 prolonged and recurrent sensitivity and reduced vision. Our goal is to dissect the molecular mechanisms for the development of stromal keratitis in EKC. Our original 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, have been retained with 2 new specific aims added: 4) to sequence all remaining HAdV-D genomes, and 5) to determine the evolutionary biology of HAdV-D. Our added experimental design will involve 3 new Co-Investigators and will utilize high throughput sequencers and cutting edge bioinformatics to develop a comprehensive view of adenoviral evolution, and pathogenesis from the genomic perspective. 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 adenoviral pathogenesis responsible for keratitis in EKC. PUBLIC HEALTH RELEVANCE: We will sequence, annotate, and analyze 22 unique human adenoviruses and thereby completely survey all the remaining viruses within human adenovirus, species D. The overall health relevance of these studies derives from our discovery and elucidation of novel mechanisms of adenovirus pathogenesis. Our focus is on corneal infections, however this research will impact the human health of all populations at increased risk for adenovirus infections, including children, office workers, immune suppressed individuals, military recruits, and even recreational swimmers.

描述（由申请人提供）：本申请根据 NOT-09-058 提交：NIH 宣布恢复法案资金可用于竞争性修订申请。人腺病毒 (HAdV) D 基因型 D8、D19、D37 和 D53 的眼部感染可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长期且反复出现的敏感性和视力下降。我们的目标是剖析 EKC 基质性角膜炎发生的分子机制。我们最初的三个具体目标 - 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保留下来，并添加了 2 个新的具体目标：4) 对所有剩余的 HAdV-D 基因组进行测序，5) 确定 HAdV-D 的进化生物学。我们新增的实验设计将涉及 3 名新的联合研究人员，并将利用高通量测序仪和尖端生物信息学，从基因组角度全面了解腺病毒进化和发病机制。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自我们对导致 EKC 角膜炎的腺病毒发病机制的新发现和阐明。公共健康相关性：我们将对 22 种独特的人类腺病毒进行测序、注释和分析，从而全面调查人类腺病毒 D 种中的所有剩余病毒。这些研究的整体健康相关性源自我们对腺病毒发病机制的新发现和阐明。我们的重点是角膜感染，但这项研究将影响所有腺病毒感染风险较高人群的人类健康，包括儿童、办公室职员、免疫抑制个体、新兵，甚至休闲游泳运动员。