Single-molecue study on GPIb-alpha and von Willebrand factor mediated platelet adhesion and signal triggering

Ju, Lining

Title:

Single-molecue study on GPIb-alpha and von Willebrand factor mediated platelet adhesion and signal triggering

dc.contributor.advisor	Zhu, Cheng
dc.contributor.author	Ju, Lining
dc.contributor.committeeMember	Dong, Jing-fei
dc.contributor.committeeMember	Curtis, Jennifer E.
dc.contributor.committeeMember	Taylor, W. Robert
dc.contributor.committeeMember	McIntire, Larry V.
dc.contributor.department	Biomedical Engineering (Joint GT/Emory Department)
dc.date.accessioned	2015-01-12T20:28:59Z
dc.date.available	2015-01-13T06:30:04Z
dc.date.created	2013-12
dc.date.issued	2013-11-12
dc.date.submitted	December 2013
dc.date.updated	2015-01-12T20:28:59Z
dc.description.abstract	The binding between the 45 kDa N-terminal domain of the a subunit of the GPIb-IX-V complex (GPIbαN) on the platelet membrane and the A1 domain of von Willebrand factor (VWF-A1), a multimeric protein circulating in the plasma, plays a key role in platelet adhesion and thrombus initiation at sites of cut-injury and atherosclerotic plaque rupture where blood vessels are subjected to high haemodynamic shear. A fundamental yet unresolved issue is how haemodynamic force upregulates this interaction (binding kinetics) and how a mechanical stimulus is translated into a biochemical signal (mechanotransduction). In order to address above issues, we setup a new biomembrane force probe (BFP) with the drifting reduction, temperature control and concurrent fluorescence imaging. My research findings are summarized into three aims: 1. VWF regions surrounding A1 hinder A1-GPIbα interaction at zero force, which is relieved by increasing force that stabilizes the interaction, giving rise to a VWF-GPIbα catch bond. 2. Three transport-related physical factors: receptor-ligand separation distance, Brownian motion and diffusivity govern the VWF-GPIbα association. 3. Mechanical force and structural variation regulate platelet signaling via the engagement duration of GPIbα mechanosensor. My thesis study advances our understanding of the biophysical and structural basis of how the VWF activation, its interaction with GPIbα and signal transduction are regulated by force when platelets' haemostatic functions are most needed.
dc.description.degree	Ph.D.
dc.embargo.terms	2014-12-01
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/1853/52953
dc.language.iso	en_US
dc.publisher	Georgia Institute of Technology
dc.subject	Platelet
dc.subject	GPIb
dc.subject	VWF
dc.subject	Single molecule
dc.subject	BFP
dc.subject	Mechanotransduction
dc.title	Single-molecue study on GPIb-alpha and von Willebrand factor mediated platelet adhesion and signal triggering
dc.type	Text
dc.type.genre	Dissertation
dspace.entity.type	Publication
local.contributor.advisor	Zhu, Cheng
local.contributor.corporatename	Wallace H. Coulter Department of Biomedical Engineering
local.contributor.corporatename	College of Engineering
relation.isAdvisorOfPublication	d28f1a84-f07d-40ec-bed3-60bc4c140551
relation.isOrgUnitOfPublication	da59be3c-3d0a-41da-91b9-ebe2ecc83b66
relation.isOrgUnitOfPublication	7c022d60-21d5-497c-b552-95e489a06569
thesis.degree.level	Doctoral