Thomas J. Brett, Ph.D.

Assistant Professor
Internal Medicine
Pulmonary & Critical Care Medicine
Cell Biology and Physiology
Biochemistry and Molecular Biophysics

Biochemistry, Biophysics, and Structural Biology Program
Immunology Program

  • 314-747-0018

  • 314-747-0049

  • 314-362-9047

  • 8052

  • CSRB 10046 & 10042

  • tbrett@wustl.edu

  • http://brettlab.dom.wustl.edu/

  • biophysics, crystallography, molecular medicine, asthma, mucosal immunology, Alzheimer`s disease, endocytosis, receptor trafficking, structural biology, structure based drug design

  • The molecular basis of lung diseases and drug development using structural biology tools

Research Abstract:

Chronic obstructive lung diseases such as asthma and COPD afflict millions worldwide. The development of effective treatments requires detailed knowledge of the molecular mechanisms that produce disease pathology. Our research interests are focused on three main areas of acute and chronic lung disease pathogenesis: 1) molecular mechanisms of mucus overproduction; 2) host/respiratory virus interactions and the anti-viral response; and 3) innate immune signaling in chronic obstructive lung diseases. To approach these questions, we have taken a multidisciplinary approach using the tools of structural biology (X-ray crystallography), protein biochemistry and biophysical methods, computational biology, cell biology, and molecular immunology to study in detail the proteins involved in producing these disease states. The synthesis of information gained from these methodologies facilitates the design of therapeutic biologics (proteins, peptides, and antibodies) or small molecule drugs via high throughput screening, virtual screening (computational docking), and structure-based drug design. We collaborate closely with cell biologists, geneticists, medicinal chemists, and clinicians within the Pulmonary Division to pursue these goals from bench to bedside.

Selected Publications:

Sala-Rabanal, M, Yurtsever, Z, Berry, KN, Nichols, CG, Brett, TJ. Modulation of TMEM16A Channel Activity by the Von Willebrand Factor Type A (VWA) domain of the Calcium-Activated Chloride Channel Regulator 1 (CLCA1). Journal of Biological Chemistry. 1-11. April 18 (2017).

Kober, DL, Brett, TJ. TREM2-ligand interactions in health and disease. Journal of Molecular Biology.1-23. April 18 (2017).

Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. 5 (2016). PMCID: PMC5173322.

Yurtsever Z, Patel DA, Kober DL, Su A, Miller CA, Romero AG, Holtzman MJ, Brett TJ. First comprehensive structural and biophysical analysis of MAPK13 inhibitors targeting DFG-in and DFG-out binding modes. Biochim Biophys Acta. 1860:2335-44 (2016). PMCID: PMC5011001.

Sala-Rabanal M, Yurtsever Z, Nichols CG, Brett TJ. Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells. eLife. 4 (2015). PMCID: PMC4360653

Wu K, Byers DE, Jin X, Agapov E, Alexander-Brett J, Patel AC, Cella M, Gilfilan S, Colonna M, Kober DL, Brett TJ, Holtzman MJ. TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med. 212:681-697 (2015).

Yurtsever Z, Sala-Rabanal M, Randolph DT, Scheaffer SM, Roswit WT, Alevy YG, Patel AC, Heier RF, Romero AG, Nichols CG, Holtzman MJ, Brett TJ. Self-cleavage of human CLCA1 by a novel internal metalloprotease domain controls calcium-activated chloride channel activation. J Biol Chem. 2012, 287: 42138-42149.
(Selected as JBC Paper of the Week)

Alevy YG, Patel AC, Romero AG, Patel DA, Tucker J, Roswit WT, Miller CA, Heier RF, Beyers DE, Brett TJ, Holtzman MJ. IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J Clin Invest. 2012, 122: 4555-4568.

Swiecki, M., Omattage, NS, Brett, TJ. BST-2/Tetherin: Structural biology, viral antagonism, and immunobiology of a potent host antiviral factor, Mol. Immun., 2013, 54: 132-139, epub Dec. 28, 2012.

Swiecki M, Scheaffer SM, Allaire M, Fremont DH, Colonna M and Brett TJ. Structural and biophysical analysis of BST-2/tetherin ectodomains reveal an evolutionary conserved design to inhibit virus release. Journal of Biological Chemistry 2011 Jan 28;286(4):2987-97. Epub 2010 Nov 17.

Last Updated: 4/25/2017 10:06:45 AM

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