Research Interests
- molecular biomechanics and biophysics of biological adhesion
- platelet adhesion and thrombosis
- bacterial adhesion and biofilms
- computational nano- and micro-mechanics simulations
- design of reversible and nonfouling biomedical adhesives
Contact Information
Department of Bioengineering
University of Washington
Box 355061
William H. Foege Building, Room N430P
Phone: 206-616-3947
Fax: 206-685-4434
E-mail: wendyt@u.washington.edu
Lab homepage: http://faculty.washington.edu/wendyt/index.html
Research Description
I am interested in understanding how proteins are mechanically regulated, with a particular emphasis on adhesion. Many proteins experience mechanical force from fluid flow, cytoskeletal forces, or other sources. This might be expected to weaken adhesion, by tearing the bound molecules away from each other, but we study situations where force or fluid flow enhances adhesion. Our lab group asks basic biophysics questions as well as questions about the medical significance of the research and about technological applications.
One project in the lab involves studying a bacterial adhesive protein called FimH that is activated by mechanical force. This means it acts like a catch-bond that binds longer when you try to pull it off. Bacteria binding through FimH will only bind firmly at high levels of fluid flow, and will roll across the surface or detach if the flow is stopped. FimH is expressed on most of our intestinal bacteria and is involved in urinary tract infections. One thrust of this research is to understand how bacteria use catch bonds to form biofilms in the presence of flowing bodily fluids. We hope to learn methods to prevent biofilms from forming on indwelling medical devices such as urinary catheters since this can lead to sepsis and death as well as requiring costly and sometimes dangerous replacement of the implant.
A second project involves thrombosis, or blood clots. Most mechanisms through which blood can clot do not function well at high shear stress, which is encountered in spurting wounds. One mechanism – binding of platelets to the blood protein von Willebrand Factor – not only works in this condition, but it actually requires high shear to be activated. We are seeking to understand the molecular basis of this shear activated thrombosis. Unfortunately, high shear is also encountered in advanced atheroschlerosis, where plaques restrict vessels, so this protective mechanism can cause blood clots in these vessels that in turn can cause a heart attack or stroke. We hope that understanding this mechanism will lead to minimally invasive ways to protect patients with atheroschlerosis from deadly blood clots.
Finally, my lab is interested in pursuing technological applications of force- or shear-enhanced adhesion. A catch-bond is the ultimate in reversible adhesion -- it only binds when you need it. We are pursing applications of FimH in reversible adhesion and are applying what we have learned from FimH to design novel mechanically regulated proteins. Finally, mechanically sensitive proteins function as nanoscale mechanical actuators, and we can learn engineering principles from them for nanotechnology applications beyond adhesive technology.
We use a combination of computational and experimental tools to understand the biophysics as well as to design engineering applications. We use the atomic force microscope to apply force to single molecular bonds or macromolecular complexes. Microfluidic chambers apply force to single cells to show how cells adhere in flow. Course grained simulations relate the molecular properties to cellular properties in our different experiments. Finally, Molecular Dynamics simulations and Rosetta protein structure prediction allow an understanding of the structural basis of the various observed effects. Genetic mutation of the proteins can link the structural simulations to all the experimental methods. While some group members do all simulations or all experiments, many do both and an interest and understanding about both approaches is very helpful for success in this interdisciplinary research.
Teaching Activities
Honors and Awards
- 2007:
American Heart Association National Scientist Development Grant
- 2007: National Science Foundation CAREER Award
- 1999-2003: Whitaker Foundation Graduate Fellowship
Selected Publications
- Thomas WE. Catch Bonds in Adhesion. Ann Rev. Biomed Eng (2008; in press)
- Thomas WE. Vogel, V. and Sokurenko, E. Biophysics of Catch Bonds. Annual Review of Biophysics (2008, in press)
- Tchesnokova V, Aprikian P, Yakovenko O, LaRock, C, Kidd B, Vogel V, Thomas W, and Sokurenko E. Integrin-like allosteric properties of the catch-bond forming FimH adhesin of E. coli. J Biol Chem (2008; in press)
- Natalia Korotkova, Yi Yang, Isolde Le Trong, Ernesto Cota, Borries Demeler, Jan Marchant, Wendy E. Thomas, Ronald E. Stenkamp, Steve L. Moseley and Steve Matthews, “Binding of Dr adhesins of Escherichia coli to carcinoembryonic antigen triggers receptor dissociation” Molecular Microbiology 67(2) p 420-434 (2008)
- Aprikian P, Tchesnokova V, Kidd B, Yakovenko O, Yarov-Yarovoy V, et al. 2007. Interdomain Interaction in the FimH Adhesin of Escherichia coli Regulates the Affinity to Mannose. J Biol Chem 282: 23437-46
- Anderson, B., A. Ding, L. Nilsson, K. Kusuma, V. Tchesnokova, V. Vogel, E. Sokurenko, and W.E. Thomas, " Weak Rolling Adhesion Enhances Bacterial Surface Colonization ". J. Bac. 189(5): 1794-802.(2007)
- Thomas, W.E., "Understanding the Counterintuitive Phenomenon of Catch Bonds". Current Nanotechnology. (in press)
- Thomas, W.E., "For catch bonds, it all hinges on the interdomain region". J Cell Biol. 2006 174(7): 911-3.
- Forero, M., O. Yakovenko, E.V. Sokurenko, W.E. Thomas, and V. Vogel. 2006. Uncoiling Mechanics of Escherichia coli Type I Fimbriae Are Optimized for Catch Bonds. PLoS Biol. 4.
- Nilsson, L.M., W.E. Thomas, E.V. Sokurenko, and V. Vogel. 2006a. Elevated Shear Stress Protects Escherichia coli Cells Adhering to Surfaces via Catch Bonds from Detachment by Soluble Inhibitors. Appl Environ Microbiol. 72:3005-10.
- Nilsson, L.M., W.E. Thomas, E. Trintchina, V. Vogel, and E.V. Sokurenko. 2006b. Catch bond-mediated adhesion without a shear threshold: trimannose versus monomannose interactions with the FimH adhesin of Escherichia coli. J Biol Chem.
- Pereverzev, Y., O.V. Prezhdo, M. Forero, E. Sokurenko, and W. Thomas. 2005a. The Two-Pathway Model for the Catch-Slip Transition in Biological Adhesion. Biophys J. 89:1446-1454.
- Pereverzev, Y.V., O.V. Prezhdo, W.E. Thomas, and E.V. Sokurenko. 2005b. Distinctive features of the biological catch bond in the jump-ramp force regime predicted by the two-pathway model. Phys Rev E Stat Nonlin Soft Matter Phys. 72:010903.
- Thomas, W.E., L. Nilsson, M. Forero, E.V. Sokurenko, and V. Vogel. 2004. 'Stick-and-roll' bacterial adhesion mediated by catch-bonds. Molecular Microbiology. 53:1545.
- Forero, M., Thomas, W.E., Bland, C., Nilsson, L., Sokurenko, E.V., and Vogel, V. (2004) A Catch-Bond Based Smart Nano-Adhesive Sensitive to Shear Stress. Nano Letters: in press.
- Thomas, W.E., Trintchina, E., Forero, M., Vogel, V., and Sokurenko, E.V. (2002) Bacterial adhesion to target cells enhanced by shear force. Cell 109: 913-923.
- Krammer, A., Craig, D., Thomas, W.E., Schulten, K., and Vogel, V. (2002) A structural model for force regulated integrin binding to fibronectin's RGD-synergy site. Matrix Biol 21: 139-147.
- Vogel, V., Thomas, W.E., Craig, D.W., Krammer, A., and Baneyx, G. (2001) Structural insights into the mechanical regulation of molecular recognition sites. Trends Biotechnol 19: 416-423.
- Thomas, W.E., and Glomset, J.A. (1999a) Affinity purification and catalytic properties of a soluble, Ca2+-independent, diacylglycerol kinase. Biochemistry 38: 3320-3326.
- Thomas, W.E., and Glomset, J.A. (1999b) Multiple factors influence the binding of a soluble, Ca2+-independent, diacylglycerol kinase to unilamellar phosphoglyceride vesicles. Biochemistry 38: 3310-3319.
|
