Title:
The force regulation on binding kinetics and conformations of integrin and selectins using a bio-membrane force probe

dc.contributor.advisor Cheng, Zhu
dc.contributor.author Chen, Wei en_US
dc.contributor.committeeMember Degertekin Levent
dc.contributor.committeeMember Evans Evan
dc.contributor.committeeMember Garcia Anes
dc.contributor.committeeMember McCarty Nael
dc.contributor.department Mechanical Engineering en_US
dc.date.accessioned 2010-06-10T15:10:46Z
dc.date.available 2010-06-10T15:10:46Z
dc.date.issued 2009-04-03 en_US
dc.description.abstract Cell adhesion plays an important role in inflammation and immunological responses. Adhesion molecules (e.g., selectins and integrins) are key modulators in mediating these cellular responses, such as leukocyte trafficking under shear stress. In this thesis, we use a bio-membrane force probe (BFP) to study force regulation on kinetics and conformations of selectin and LFA-1 integrin. A new BFP was built up, and a new assay, using thermal fluctuation of the BFP, was developed and used to monitoring selectins and their ligands association and dissociations. The new BFP was also used to investigate the force and force history dependence of selectin-ligand interactions. We found tri-phasic transition of force-dependent off-rates and force-history dependence of selectin/ligaind interactions. The BFP was also used to characterize force-dependent lifetimes of the LFA-1-ICAM-1 interaction. We found that LFA-1/ICAM-1 bonds behaved as catch bond and that LFA-1-ICAM-1's catch bonds were abolished blocking the downward movement of αA domain α7 helix. Finally, the BFP was applied to dynamically probe the global conformational changes of LFA-1 and to characterize force-regulated transitions among different conformational states on a living cell. We observed dynamic transitions of LFA-1 between extended and bent conformations on living cells. The observed average distance change of LFA-1's extensions was about 18nm, while that of the bending was only about 14nm. We also found that forces could facilitate extension but they slow down the bending of LFA-1. The observed transition time of extension was less than 0.1s, while that of contraction was longer than 0.2s. Our observations here are the first in-situ evidence to demonstrate how integrins dynamically transit different conformations and how force regulates these transitions. en_US
dc.description.degree Ph.D. en_US
dc.identifier.uri http://hdl.handle.net/1853/33814
dc.publisher Georgia Institute of Technology en_US
dc.subject Kinetics en_US
dc.subject Conformational change en_US
dc.subject Thermal fluctuation en_US
dc.subject BFP en_US
dc.subject Cell adhesion en_US
dc.subject Integrin en_US
dc.subject Selectin en_US
dc.subject.lcsh Integrins Conformation
dc.subject.lcsh Selectins Conformation
dc.subject.lcsh Membranes (Biology)
dc.subject.lcsh Shear (Mechanics)
dc.subject.lcsh Dynamics
dc.subject.lcsh Force and energy
dc.title The force regulation on binding kinetics and conformations of integrin and selectins using a bio-membrane force probe en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.corporatename George W. Woodruff School of Mechanical Engineering
local.contributor.corporatename College of Engineering
relation.isOrgUnitOfPublication c01ff908-c25f-439b-bf10-a074ed886bb7
relation.isOrgUnitOfPublication 7c022d60-21d5-497c-b552-95e489a06569
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