Principal Investigator: Lee Ratner, MD, Washington University
Transgenic mice with HTLV-1 Tax expressed under the regulation of the granzyme B promoter develop a lymphoproliferative disorder of NK cells and lytic bone lesions. Tax is a potent transcriptional trans-activator, functioning through cellular transcription factors, including nuclear factor kappa B (NFkB). Tax transgenic tumors exhibit high levels of NFkB activity and NFkB inhibitors induce apoptosis of Tax transgenic tumor cells ex vivo.
The first aim of the study is to examine the inflammation and gene expression by studying the inflammatory stimuli on TCR/LTR-luc and TCR/LTR-luc/GzB-Tax mice. The second aim of the study will examine the regulation of viral latency by HTLV antisense expression, which will involve a study of HBZ RNA activities in culture as a model for microRNA activity. The third aim of this study is a combined influence of regulators of viral and cellular gene expression. This aim would be a result of mating HBZ transgenic mice with TCR/LTR-luc and TCR/LTR-luc/GzB-Tax mice.
These studies use Tax transgenic mice as a model system applicable to understanding the biology of many human malignancies. It is a unique animal model in which to explore the molecular basis of bone metastases. Moreover, it provides an opportunity to examine the efficacy of NFkB inhibitors as a form of cancer treatment.