Present Position and Address

8.138 Medical Research Building
Telephone: (409) 772-2824
Fax: (409) 772-8709
E-mail: arbrasie@utmb.edu
Mail Route: 1060

B.A. 1979 University of California, San Diego
M.D. 1983 University of California, San Francisco

RESEARCH INTERESTS:

A central problem in cellular biology is to understand how cells transduce signals in the extracellular environment to produce changes in the expression of homeostatic genes. Extracellular signals, taking the form of hormones or environmental signals (such as viral infection, heat, uv-light) alter signal transduction pathways that ultimately result in the activation of a limited set of DNA-binding proteins. These transcription factors, in turn, activate expression of genetic networks plays a dominant role in cellular response to stress and the pathobiology of numerous human disease states including inflammation, hypertension, wound repair, and malignancy.

Work in my laboratory has concentrated on cellular mechanisms of genetic responses to inflammatory hormones in the liver (the hepatic acute-phase response) and the respiratory epithelium (the pulmonary cytokine cascade).

Our lab has defined mechanism for activation of a key signal transduction molecule that mediate the transcriptional activation of the acute phase reactants. The hepatic acute-phase response is seen following acute viral or drug-induced hepatitis, heavy metal poisoning, or systemic bacterial infection. Inflammatory hormones, such as tumor necrosis factor-a (TNFa), initiates de novo transcription of genetic networks through activating nuclear translocation of the latent cytoplasmic nuclear factor-kB (NF-kB) transcription factor. NF-kB is sequestered in the cytoplasm by association with inhibitory proteins termed IkBs. After TNFa stimulation IkB is rapidly proteolyzed, releasing NF-kB to enter the nucleus and stimulate transcription of acute-phase reactants. Our lab was the first to show the inducible degradation of the IkB protein is mediated by cytosolic calcium-activated neutral endoproteases (calpains).

A separate model under study in my laboratory is the mechanisms for the pulmonary cytokine cascade activated by Respiratory syncytial virus (RSV) infection. RSV is a ubiquitous pathogen that infects virtually 100% of the US population before the age of three and is responsible for 100,000 hospitalizations annually. Apart from its acute effects, RSV infection is etiologically linked to airway hyper-reactivity (asthma) in children. RSV produces a pronounced inflammatory response in airways of children with active infection; this is a consequence of inflammatory mediators (cytokines) produced by airway epithelial cells. These cytokines recruit and activate various populations of immune cells into the respiratory mucosa. We have demonstrated that RSV-infected alveolar epithelial cells inducibly transcribe and secrete IL-8. IL-8 gene expression is mediated and absolutely dependent on the nuclear translocation of the NF-kB subunit, Rel A. We are presently investigating the mechanisms for NF-kB activation of IL-8 through studies on promoter assembly and characterization of NF-kB dependent gene networks using microarray technology. These studies are also part of a NIAID sponsored Asthma and Allergic Diseases Research Center grant.

1. Sherman,C.T. and Brasier, A.R. Role of signal transducers and activators of Transcription 1 and 3 in inducible expression of human angiotensinogen gene by interleukin-6. Molecular Endocrinology 2001; 15:441-447.
2. Casola, A. Garofalo, R.P., Haeberle, H., Elliott, T., Jamaluddin, M., Brasier, A.R. Mulptiple inducible cis elements control RANTES transcription in alveolar epithelial cells infected with RSV. Journal of Virology 2001; 75:6428-6429.
3. Lu, Y., Jamieson, L., Brasier, A.R. and Fields, A.P. NF-kB/Rel A transactivation is required for atypical protein kinase Ci-mediated cell survival. Oncogene 2001; 20:4777-4792.
4. Brasier, A.R., Lu, M., Hai, T., Lu, Y. and Boldogh, I. Inducible expression of cytoplasmic BCL-3 in an autoregulatory loop terminating NF-kB action. Journal of Biological Chemistry 2001; 276:32080-32093.
5. Zhang, Y, Luxon, B.A., Casola, A., Garofalo, R.P., Jamaluddin, M. and Brasier, A.R. Expression of RSV-induced chemokine gene networks in lower airway epithelial cells revealed by cDNA microarrays. Journal of Virology 2001; 75-9044-9058.
6. Brasier, A.R. Retriever and compare table, two informatics tools for data analysis of high density oligonucleotide arrays. BioTechniques 2002; 32-100-109.
7. Ray, S., Sherman, C.T., Lu, M. and Brasier, A.R. Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/CBP coactivator recruitment and histone acetyltransferase activity. Molecular Endocrinology 2002; 16:824-836.
8. Tian, B., Zhang, Y., Luxon, B.A., Garofalo, R.P., Casola, A., Sinha, M. and Brasier, A.R. Identification of NF-kB dependent gene networks in respiratory syncytial virus-infected cells. Journal of Virology 2002; 76:6800-6814.