Microbiology, Immunology & Molecular Genetics

Office: (859) 257-5167 Fax: (859) 257-8994 Lab: (859) 323-5089 Email: bspear@uky.edu

Brett Spear, Ph.D.
Professor

Doctoral Studies: University of Pennsylvania.
Postdoctoral: Princeton University.
Member of: Graduate Center for Toxicology, Graduate Center for Nutritional Sciences, Integrated Biomedical Sciences (IBS) Graduate Program

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 recently cloned Zhx2 as a regulator of AFP expression.  We are currently investigating the role of Zhx2 in the control of AFP as well as other hepatic genes.  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 are interested in the link between these chemicals, nutritional status, oxidative stress, transcription factors, epigenetic events, and liver cancer.  These studies emphasize the use of transgenic and gene knock-out mice.

Selected Recent Publications:

Glauert, H.P., K. Calfee-Mason, Y. Li, V. Nilakantan, M.L. Twaroski, J. Tharappel and B.T. Spear.  (2009) The Role of NF-kB in PPARa-mediated carcinogenesis.  PPAR Research, Epub Jan 29, 2009. 

Glauert, H.P., J.C. Tharappel, S. Banerjee, L.S. Chan, I. Kania-Korwel, H.-J. Lehmler, E.Y. Lee, L.W.  Robertson, and B.T. Spear.  (2008)  Inhibition of the promotion of hepatocarcinogenesis by 2,2’,4,4’,5,5’-Hexachlorobiphenyl (PCB-153) by the deletion of the p50 Subunit of NF-kB in mice.  Toxicol Appl Pharmacol. 232:302-308.

Butler, J.E. and B.T. Spear.  (2008)  Normal intestinal epithelial cell differentiation in the absence of p21 and p27: new insights from old knock-out mice.  Cancer Biol Ther. 7:880-881.

Glauert, H.P., J.C. Tharappel, Z. Lu, D. Stemm, S. Banerjee., L.S. Chan, E.Y. Lee, H.-J. Lehmler, L.W. Robertson and B.T. Spear.  (2008)  Role of oxidative stress in the promoting activities of PCBs.  Environm. Toxicol. and Pharmacol. 25:247-250.

Perincheri, S., D.K. Peyton, M. Glenn, M.L. Peterson, and B.T. Spear.  (2008)  Characterization of the ETnII-a endogenous retroviral element in the BALB/cJ Zhx2Afr1 allele.  Mammalian Genome. 19: 26-31.

Morford, L.A., C. Davis, L. Jin, A. Dobierzewska, M.L. Peterson, and B.T. Spear.  (2007)  The oncofetal gene Glypican 3 is regulated in the postnatal liver by Zinc  Fingers and Homeoboxes Protein 2 and in the regenerating liver by Alpha-fetoprotein regulator  2.  Hepatology, 46(5):1541-1547.

Zhao Y, R. Burikhanov, S. Qiu, S.M. Lele, C.D. Jennings, S. Bondada, B. Spear, and V.M. Rangnekar.  (2007)  Cancer resistance in transgenic mice expressing the SAC module of Par-4.  Cancer Res. 67:9276-9285.

Spear, B.T., L. Jin, S. Ramaswamy, and A. Dobierzewska.  (2006)  Transcriptional control in the mammalian liver:  Liver development, perinatal repression, and zonal gene regulation.  Cellular and Molecular Life Sciences  63:2922-2938.