Research statement: My research interests are in the area of mammalian gene regulation; in particular, we are interested in transcriptional regulation in the liver during development and disease. Two experimental systems are being used for these studies. First, liver-specific regulation of the mouse alpha-fetoprotein (AFP) gene is being investigated using biochemical and molecular genetic strategies in tissue culture cells and transgenic mice. In vitro biochemical studies allow us to characterize the interplay between transcription factors and AFP regulatory elements such as the AFP promoter and enhancers. AFP constructs are analyzed in liver cell lines to further explore the consequences of these interactions. Finally, to fully understand aspects of AFP regulation, we introduce AFP DNA constructs into the mouse germline to produce transgenic animals. Using the tools and resources of the human genome project, we are also using a genetic approach to clone Afr1, a regulator of AFP expression. Our long-term objective is to understand the complex processes that control gene expression during mammalian development and will ultimately elucidate how specific organs such as the liver arise from a precursor cell population.
We are also interested in how transcription factors are involved in the response to agents that cause liver damage and/or liver cancer. In particular, we are studying the response to peroxisome proliferators, phenobarbital, and PCBs. We have focused on the link between these chemicals, oxidative stress, and the transcription factor NF-kB. Using transgenic and gene knock-out mice, we are using methods to block NF-kB activation specifically in the liver. These mice provide an in vivo model system to study the role of NF-kB in hepatocarcinogenesis and the response to liver-damaging agents. |
