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.
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.
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