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The research in my laboratory follows three main themes:
         
  • studies on the mechanisms of nuclear transport of plasmids
  • development of nuclear targeting plasmid vectors for gene therapy of the lung, eye and vasculature.
  • Effects of cyclic stretch on gene transfer and expression in cultured cells and tissues
Despite all of the hype regarding gene therapy, at present, gene therapy is a dream due to insufficient levels of gene transfer and expression at desired sites. One way to increase gene expression is to target more DNA to the cell nucleus. Since the nucleus is the site of transcription, without the translocation of plasmid DNA into the nucleus, no gene expression, or "gene therapy" can take place. Ongoing projects in my laboratory are studying the mechanisms of plasmid nuclear entry and exploiting what we learn to improve gene therapy.

We have shown that plasmids are able to enter the nucleus in a sequence-specific manner that appears to be mediated by transcription factor binding. My lab is interested in identifying the proteins required for this activity and the regulation of their nuclear import. Based on our model, we have created cell-specific plasmids by incorporating DNA sequences that bind to cell-specific transcription factors. At present, we have examples of smooth muscle and endothelial cell-targeting vectors that we hope to use for the treatment of vascular proliferative diseases, and we are working to expand our repertoire to selectively target expression to any desired cell or tissue.

We also are developing methods for extracellular delivery of non-viral vectors in animal models for disease. Using electroporation, we have obtained very high levels of gene expression in the vasculature, lungs, and eyes of animals. Our next goal is to combine our studies on cell-specific plasmid nuclear import with this delivery method to restrict expression to individual cell types and begin to focus on attacking disease states.

For more detailed information on our research, follow the links below:
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dean@northwestern.edu
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