Allan R. Brasier, M.D.Dr. Brasier

Professor, Dept. of Biochemistry and Molecular Biology, Dept. of Internal Medicine, Sealy Center for Molecular Medicine; Sealy Center for Cancer Cell Biology

Nelda C. & H.J. Lutcher Stark Distinguished Chair in Endocrinology
Director, Sealy Center for Molecular Medicine
Associate Director, NHLBI Proteomics Center
University of Texas Medical Branch
301 University Blvd. Galveston, TX 77555-1060
Phone (409)-772-2824
Email: arbrasie@utmb.edu
URL: http://www.bioinfo.utmb.edu/Brasier_Lab/

Research Summary:

A number of common human chronic diseases are due to chronic inflammation as an underlying mechanism, notably atherosclerotic heart disease and asthma. Work in my laboratory has concentrated on cellular signaling pathways activated by inflammation with the goal of being able to selectively modify these pathways as treatment modalities.

One of our major areas of concentration is to understand signaling pathways controlling the “master” regulator of inflammation known as nuclear factor-kB (NF-kB). NF-kB is controlled by a diverse set of signaling pathways, which affect both its translocation into the nucleus, as well as producing specific phosphorylation which control its activity. Our lab was one of the first to show that a blood pressure regulating hormone known as angiotensin II activates NF-kB in smooth muscle cells, producing chronic vascular inflammation. In fact, vascular inflammation is now known to be a major, independent risk factor for the development of atherosclerosis. In recent work, we have further extended our findings to implicate the GTPase Rho A as a controller of angiotensin II-induced NF-kB signaling mediated by NF-kB phosphorylation. We are currently pursuing animal studies to determine whether agents that affect the RhoA-NF-kB pathway can be used to treat atherosclerosis and other types of heart disease.

We have also been investigating the key steps NF-kB uses to activate target genes once it enters the nucleus. Using mRNA profiling studies, our lab was the first to demonstrate that NF-kB activates waves of gene expression, with each wave controlling distinct biological processes. This work has led to fundamental new concepts in how NF-kB activity is controlled after it binds to its target genes, and we have implicated members of the cyclin dependent kinases that are critical for NF-kB by enhancing the process of transcriptional elongation. We are investigating whether inhibition of cyclin dependent kinases can be used as anti-inflammatory agents in models of airway inflammation.

Currently, we are developing exciting new technology using high throughput mass spectrometry to define the protein interaction network of the NF-kB signaling pathway and how it changes in response to various inflammatory stimuli. These studies will identify novel interactions to which new therapeutics can be developed to modify inflammatory disease, including asthma, heart disease and diabetes.

Selected Publications

  1. Brasier, AR, Spratt, H. Wu, Z., Boldogh, S., Zhang, Y., Garofalo, R.P., Casola, A., Pashmi, J., Haag,A., Luxon, B., and Kurosky, A. Nuclear Heat Shock Response and Novel Nuclear Domain 10 Reorganization in Respiratory Syncytial Virus-Infected A549 Cells Identified By High Resolution 2D Gel Electrophoresis. J. Virol., 2004, 78: 11461-11476.
  2. Choudhary, S., Boldogh, I., Garofalo, R.P., Jamaluddin, M., and Brasier, A.R. RSV influences NF-kB dependent gene expression through a novel pathway involving MAP3K14/NIK expression and nuclear complex formation with NF-kB2. J. Virol., 2005, 79(14): 8948-8959.
  3. Tian, B., Nowak, D., Jamaluddin, M., Wang, S. and Brasier, A.R. Identification Of Direct Genomic Targets Downstream Of The NF-kB Transcription Factor Mediating TNF Signaling. J.Biol. Chem., 2005; 280:17435-17448.
  4. Ray, S., Boldogh, I., and Brasier, A.R. STAT3 NH2-Terminal Acetylation Is Activated By The Hepatic Acute-Phase Response And Required for IL-6 Induction of Angiotensinogen. Gastroenterology, 2005; 129:1616-1632.
  5. Tian, B., Nowak, D., and Brasier, A.R. A TNF Induced Gene Expression Program Under Oscillatory NF-kB Control. BMC Genomics, 2005; 6:137.
  6. Nowak, D.E., Tian, B., Brasier, A.R. Novel Two-Step Cross-linking method for Identification of NF-kB Gene Network by Chromatin Immunoprecipitation. Biotechniques, 2005; 39(5): 715-725.
  7. Forbus, J, Spratt, H., Wiktorowicz, J., Wu, Z., Boldogh, I., Denner, L., Kurosky, A., Brasier,R.C., Luxon, B., Brasier A.R. Functional Analysis Of The Nuclear Proteome Of Human A549 Alveolar Epithelial Cells By HPLC- High Resolution 2D Gel Electrophoresis. Proteomics, 2006; 6: 2656-2672.
  8. Cui, R., Tieu, B., Recinos, A., Tilton, R.G. and Brasier, A.R. RhoA Mediates Angiotensin II-Induced Phospho-Ser536 NF-kB/RelA Subunit Exchange On The IL-6 Promoter In VSMC, Circ. Research, 2006; 99:723-730.
  9. Recinos, A. III, LeJeune, W., Sun, H., Tieu, B., Lu, M., Boldogh, S., and Brasier, A.R.  Angiotensin II Induces IL-6 Expression and the Jak-STAT3 Pathway in Aortic Adventitia of LDL Receptor-Deficient Mice.  Atheriosclerosis, 194: 125-133, 2007.
  10. Liu, P., Choudhary, S., Jamaluddin, M., Li, K., Garofalo, R.P., Casola, A., and Brasier, A.R. Respiratory Syncytial Virus Activates Interferon Regulatory Factor-3 in Airway Epithelial Cells by Upregulating a RIG-I-Toll like receptor-3 Pathway. Journal of Virology, 81: 1401-1411, 2007.
  11. Jamaluddin, M., Wang, S., Boldogh, I., Tian, B., and Brasier, A.R. TNF-a-Induced NF-kB/Rel A Ser276 Phosphorylation And Enhanceosome Formation On The IL-8 Promoter Is Mediated By A Reactive Oxygen Species (ROS)-Dependent Pathway, Cellular Signalling, 9:1419-1433, 2007.
  12. Choudhary, S., Lu, M., Cui, R. and Brasier, A.R. Involvement of a Novel Rac/RhoA GTPase-NF-kB Inducing Kinase (NIK) Signaling Pathway Mediating Angiotensin II-Induced RelA Transactivation.  Molecular Endocrinology, 2007, 21: 2203 - 2217.
  13. Lipniacki, T., Puszynski, K., Paszek, P., Brasier, A.R., Kimmel, M. Stochastic robustness of NF-kappaB signalling:  Low dose TNF stimulation.  BMC Bioinformatics, 8:376, 2007.
  14. Brasier, A.R, Victor, S., Boetticher, G.D., Ju, H, Lee, C., Bleecker, E.R., Castro, M.,  Busse, W.W. and Calhoun W.J.  Molecular Phenotyping Of Severe Asthma Using Pattern Recognition of Bronchoalveolar Lavage-Derived Cytokines 2007, Journal of Clinical Allergy and Immunology, in press.
Reviews:

Brasier AR, Recinos A, Eledrisi MS. “Vascular inflammation and the renin angiotensin system”. Invited Brief Review, Arteriosclerosis, Thrombosis and Vascular Biology, 2002; 22:1257-1266.

Tian, B., and Brasier, A.R. (2006). The Nuclear Factor-kB (NF-kB) Gene Regulatory Network. Microarrays and Transcription Networks, Edited by Frances Shannon and Sudha Rhao. © 2005, Landes Bioscience, Eurekah.com.

Brasier, A.R. † (2006).  The NF-kB Regulatory Network.  Cardiovascular Toxicology, 6(2):111-130.

Brasier, A.R., Liu, P., Tian, B., and Choudhary.  Signaling pathways in the host cell response to RSV infection.  In Host Gene Responses to RNA Viral Infection, Edited by Decheng Yang, World Scientific Publishing, 2008.