This is a resubmission application for the renewal of a laboratory-based Program on tumor viruses. This Program has maintained high productivity and close interactions for the last 20 years under the direction of Daniel DiMaio. In the current version, the two projects headed by Dr. DiMaio have been replaced with a single related project, allowing the addition of an exceptional new project leader, Akiko Iwasaki. All four projects in thi Program focus on various related aspects of tumor virology, including regulation of viral and cellular gene expression, virus entry, and engagement of cellular innate immune defenses. Dr. Miller will analyze new and unexpected biological activities of the major transcriptional regulator of Epstein Barr virus, including collaborative experiments with Dr. Steitz to study virus host shut off. Dr. DiMaio will determine the mechanism by which the cellular protease ?-secretase supports human papillomavirus infection of epithelial cells. Dr. Steitz will continue her analysis of herpesvirus non-coding RNAs and their contribution to regulation of cellular gene expression. Dr. Iwasaki will examine interactions of human papillomavirus with the innate immune system, based in large part on studies carried out in the DiMaio laboratory. Numerous collaborations among the project leaders are already underway or proposed. In addition, the protein expression core has been replaced by a bioinformatics core serving the exploding bioinformatics needs of the projects. In the past project period, the Program published 44 peer-reviewed papers. Seven papers were jointly authored by the project leaders and/or supported by more than one project, and another jointly authored manuscript has been submitted. A number of mechanisms are in place to ensure continued integration: monthly meetings of the laboratory leaders and staffs, dedicated meetings of the project leaders, monthly meetings of the HPV and herpesvirus subgroups of the projects, and an annual retreat of the entire Program. We have also reconstituted external and internal boards to provide advice to the Program. These activities are coordinated through the administrative core. In addition to these Program-specific activities, there are many informal but important interactions within the group such as joint teaching efforts, virology faculty lunches, and graduate student committees. The Yale Cancer Center is another important venue of interaction. It supports essential shared resources, sponsors monthly Molecular Virology Research-in-Progress meetings, and hosts Yale Cancer Center Grand Rounds. In addition, all of the project leaders are members of the Molecular Virology Program of the Yale Cancer Center and participate in the Microbiology Graduate Program.
This is a multi-investigator, laboratory-based grant dedicated to determine the basic mechanisms of how tumor viruses replicate, evade the immune system and transform cells. Understanding the molecular basis of these activities will provide the necessary knowledge to develop novel, rational approaches to inhibit infection by these viruses and prevent or treat the cancers they cause.
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