Helen M. Blau
Title
Professor
Department
Molecular Pharmacology
Research Interests
Molecular and cellular mechanisms controlling muscle differentiation and localization of mRNAs during neuromuscular development; gene therapy for neuronal damage.
Phone
723-6209
Fax
736-0080
Address
Edwards R350
Mail Code: 5332
Faculty Research Description
Research in my laboratory is directed at understanding plasticity of differentiation: how cells become and remain differentiated during development and how cell growth and differentiation go awry, using muscle as a model. We are investigating the molecular and cellular mechanisms that control growth, differentiation, and apoptosis and the defects in these mechanisms that lead to human genetic and acquired diseases such as muscular dystrophy, cardiac disease and cancer. In addition, we are developing technologies that will enable the study and treatment of such diseases by gene therapy and other modalities.
Transcriptional and post-transcriptional regulation: Recent studies in our laboratory provide insight into the regulation of gene expression in response to environmental changes. We have shown that untranslated regions of mRNAs can alter gene expression by functioning as sensors of stress, such as hypoxia which is characteristic of ischemic tissues and tumors. The use of tetracycline regulatable vectors has allowed a study of transcription mechanisms. We have found that graded responses to different concentrations of inducers can occur, and we have defined requirements for converting graded responses to all-or-none threshold responses essential for determining whether cells will grow or differentiate.
Elucidation of protein-protein interactions in signal transduction pathways: We have developed an approach for monitoring protein-protein interactions within intact cells using chimeric proteins containing a protein of interest fused to one of two complementing beta-galactosidase deletion mutants. Using this approach, it is now possible to assess immediately and directly specific protein dimerization interactions in a biologically relevant context, localized in the cell compartments in which they normally occur. Using the beta-galactosidase complementation system, we have found that membrane receptor dimerization can be efficiently monitored, providing a means for identifying agonists and antagonists via high-throughput screens of receptors such as the EGF and erbB-2 receptors that are highly expressed in certain forms of breast cancer. Such studies have also uncovered previously unrecognized mechanisms for controlling signal transduction via these receptors. This approach also shows promise in identifying genes encoding novel interacting proteins via a "mammalian two-hybrid" approach. Promotion and inhibition of angiogenesis: Of particular interest are factors that promote angiogenesis (for cardiovascular disease) or prevent angiogenesis (for cancer). Expression studies of vascular endothelial growth factor (VEGF) in vivo have revealed that it has very different effects at different levels leading either to beneficial angiogenesis in ischemic or normal muscle tissues or to pathologic hemangiomas. We are currently investigating the utility of regulated expression of such angiogenic factors in the treatment of cardiovascular disease. Tetracyclineregulatable retroviral vectors allow control of the timing and level of gene expression for use in both cultured cells and in gene therapy. Conversely, expression of angiogenic antagonists or factors such as FasL, which we showed are chemoattractive to cells of the immune system, appear useful in arresting tumor growth. Thus, my laboratory is focused on developing novel technologies to address questions of fundamental interest with a view to finding potential clinical applications, e.g. for use in gene therapy.
Rossi, F., Charlton, C.A. and Blau, H.M. (1997) Monitoring protein-protein interactions in intact eukaryotic cells by beta-galactosidase complementation. Proc. Natl. Acad. Sci., USA 94:8405-8410.
Kringstein, A.M., Rossi, F.M.V., Hofmann, A. and Blau, H.M. (1998) Graded transcriptional response to different concentrations of a single transactivator. Proc. Natl. Acad. Sci., USA 95:13670-13675.
Springer, M.L., Chen, A. S., Kraft, P. E., Bednarski, M. and Blau, H. M. (1998) VEGF gene delivery to muscle: Potential role for vasculogenesis in adults. Molecular Cell 2:549-558.
Spicher, A., Guicherit, O.M., Duret, L., Aslanian, A., Sanjines, E.M., Denko, N.C., Giaccia, A.J. and
Blau, H., (1998) Highly conserved RNA sequences that are sensors of environmental stress. Mol.
Cell. Biol. 18:7371-7382.
Rossi, F.M.V., Guicherit, O.M., Spicher, A., Kringstein, A.M., Fatyol, K., Blakely, B.T. and Blau, H.M.
(1998) Tetracycline-regulatable factors with distinct dimerization domains allow reversible growth
inhibition by p16. Nature Genetics 20:389-393.
Areas of Study
Cellular Neurobiology
Molecular Neurobiology
Developmental Neuroscience
SBRC
Ph.D.