The long-term research goal is to employ gene delivery as a tool for therapeutic applications. The objective of this application is to develop and utilize a novel gene delivery vector based on murine gammaherpesvirus 68 (MHV-68) for gene transfer to salivary glands and oral cavity. MHV-68 infects a broad range of cell types from mouse and human, including oral epithelial and salivary gland cells. Like other herpesviruses, MHV-68 has two phases in its life cycle, latency and lytic replication. In permissive cells, MHV-68 replicates robustly and generates viral particles of high titers. In non-permissive cells, it can establish persistent or latent infection, and the viral genome is maintained as an episome. A single viral protein, RTA, has been identified as a gene product that controls the MHV-68 life cycle. Therefore, the hypothesis is that the fate of MHV-68 infection may be altered through manipulating the expression and/or function of RTA and that a recombinant MHV-68 that is deficient of RTA function may persist in permissive and non-permissive cell types in vivo and serve as a basis on which to build gene delivery vectors. The hypothesis will be tested through two specific aims: 1) To construct an RTA knock-out MHV-68 virus and to characterize its ability to serve as a vector in vitro and in vivo; 2) To construct a MHV-68 virus conditionally deficient of RTA function and to examine its target cell and tissue types in vitro and in vivo. The long-term career goals are to establish and commit to a career in academic research and to make significant contributions to the treatment of oral and dental diseases through delivery of therapeutic genes. The immediate career goals during the award period are to obtain a tenure-track position, to set up a laboratory with productive environment and to gather sufficient preliminary data for a successful R01 application. Experts in the fields of virology, gene transfer and dental research have been identified as mentors, collaborators and consultants to support and ensure the success of the proposed work. Successful development of MHV-68 based gene delivery vectors, as outlined in this proposal, will help the candidate achieve her career goals and will also have broad therapeutic applications.
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