The major goals of this research project are 1) To identify EBV genes that contribute to B cell immortalization in vitro and to EBV-related lymphomagenesis in vivo, and 2) To investigate possible interactions between EBV and selected cellular genes (c-fgr protooncogene and CD23 autocrine B cell growth factor), and 3) To assess the influence of B cell differentiation on EBV-induced B cell proliferation. To accomplish our goals, malignant B cells at varying stages of differentiation will be infected with whole virus or will be transfected with selected genes (EBNA2, LMP, CD23) to identify genes that are responsible for B cell immortalization and to study the differential expression of EBV genes in early versus late stages of differentiation. These genes were chosen as most likely to immortalize based, in part, on a preliminary experiment in which we discovered high levels of transcription in an EBV-containing human lymphoma. We hypothesize that 1) Expression of one or more viral genes (possibly EBNA2 OR LMP) permit permanent growth in vitro and may contribute to viral oncogenesis in vivo; 2) EBV's effect on B cell growth could be mediated through the cellular genes c-fgr and/or CD23; and 3) B cell differentiation influences expression of EBV latent genes and outcome of EBV infection. These experiments will be carried out under the direction of Nancy Raab-Traub PhD, an established EBV researcher with expertise in molecular analysis of EBV infection. The proposed clinical investigations will be supervised by Howard Ozer MD PhD, Director of Oncology, and Dennis W. Ross MD PhD, Director of Hematopathology at the University of North Carolina at Chapel Hill.
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