Advances in understanding gene regulation have been crucial to enhancing our knowledge of many fundamental biologic processes. For instance, it is now clear that cancer is a disease that largely ensues from aberrant patterns of gene expression resulting from genetic mutations. The ability to monitor gene expression has steadily evolved such that it is now possible to examine much of the genome simultaneously using microarray technology. However, although we can now monitor entire gene regulatory circuits, available technologies are invasive and incapable of assaying gene expression in vivo. The ability to follow changes in gene expression longitudinally in vivo would provide new insights into a variety of pathophysiologic processes including tumorigenesis. Indeed, the ability to monitor tumor progression (or regression) in a non-invasive manner would greatly facilitate the development of new therapies. Towards this end, we plan to develop sensitive MicroPET imaging procedures and use them to study prostate cancer, a tumor that is essentially incurable after metastasis and is a leading cause of death in American men. Mouse models of prostate cancer have been developed that mimic many aspects of the human disease. We plan to utilize these mouse models along with MicroPET and magnetic resonance (MR) imaging to monitor prostate tumor progression longitudinally. First, we plan to enhance the utility of HSV1 thymidine kinase (TK) as a PET reporter by selecting mutants that enhance accumulation of [18F]-FHBG. Second, we will characterize the in vivo PET imaging properties of these enhanced TK enzymes using a prostate xenograft model that metastasizes to bone and lymph nodes. Finally, we will generate transgenic mice that express an optimized TK reporter gene from the prostate-specific probasin promoter or from a different locus that is highly expressed in androgen-independent prostate tumors. These mice will be mated to a mouse model of prostate cancer and tumor progression or regression in response to therapy will be monitored by MicroPET and MR imaging.
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