Research in my laboratory focuses on the problem of cell diversity. Within this general aim we have been exploring two areas of research, the molecular regulation of cell proliferation and the control of cell-specific gene expression. Our approach has been to utilize transgenic mice to develop model systems which can then be explored in molecular detail using the tools of biochemistry, molecular biology and cell culture. We have a long-term interest in the diversification of cells in the central nervous system, and thus far have focussed our efforts on a tissue in the brain, the choroid plexus epithelium (CPE). These studies are intended to form the foundation for more in-depth analyses of regulatory functions during central nervous system development in the future. While I remain committed to the academic environment, my current level of involvement in non- research activities is great and interferes with my plan to develop the avenues of research outlined above while expanding my capabilities to explore the problems in the context of developmental neurobiology. A major commitment of my time and energy to this goal is needed now. With receipt of an RCDA, my Chairman has agreed to significantly reduce my teaching load and to relieve me of all Department committees. This represents a major shift in my efforts from 50% of my time currently committed to research to 90% with an RCDA. I have benefitted from a number of productive collaborations with my local colleagues and consider this a stimulating environment. Most notably an ongoing collaboration with Jim Pipas has enhanced the productivity of our analysis on the mechanism of T antigen (T- ag) transformation in vivo. Further, the local facilities and expertise are excellent; the scientific environment in Pittsburgh is quite rich. The current research proposal focuses on our exploration of the transforming activities of SV40 T-ag. The possibility that T-ag acts to disrupt the normal function of the tumor suppressors, p53 and pRB, provides an opportunity to explore the action of these cellular proteins in growth regulation of cells within the animal. Our ultimate goal using transgenic mice is to determine the role of each T-ag sub-activity in the tumorigenesis of a variety of cell types. Our preliminary analysis of mutant forms of T-ag in the CPE indicates that multiple T-ag activities are critical for this tumorigenic phenotype and have demonstrated the feasibility of this approach to explore, in detail, the molecular mechanism of T-ag action. Specifically, this proposal aims to determine the roles of pRB, p53 and the amino terminal activity in CPE tumorigenesis (aims 1-3), determine the cooperative effects of T-ag sub-activities in the CPE (aim 4), and to explore the influence of cell type on the mechanism of T-ag- mediated tumorigenesis (aim 5).
| McCarthy, S A; Symonds, H S; Van Dyke, T (1994) Regulation of apoptosis in transgenic mice by simian virus 40 T antigen-mediated inactivation of p53. Proc Natl Acad Sci U S A 91:3979-83 |
