Arterial thrombosis occurs in conditions of high fluid flow and is mediated by the binding of platelets via their receptor Glycoprotein Ib (GPIb) to the plasma protein called von Willebrand Factor (VWF) via the A1 domain. This process is normally down-regulated to prevent spontaneous adhesion and thrombosis, but is activated by high shear stress. The proposed work will test the hypothesis that binding of GPIb to A1 is down-regulated by the neighboring domains or flanking regions within VWF, so that VWF displays interdomain auto-inhibition. It will also test the hypothesis that mechanical force associated with high shear stress activates platelet binding by pulling these regulatory regions away from the A1 domain to relieve the auto- inhibition. The final hypothesis to be tested is that conditions that increase the spontaneous binding of platelets to VWF, including type 2B von Willebrand disease, do so by damaging the normal interdomain auto-inhibition. Regulatory domains and elements within VWF will be identified by cloning different regions of VWF and determining the adhesive behavior of both soluble and surface-immoblized molecules. The effect of mechanical force and shear stress on this regulation will be determined using an atomic force microscope and microfluidics after immobilizing the molecules in an oriented fashion.

Public Health Relevance

Thrombosis prevents bleeding at the site of damaged blood vessels but can also lead to heart attacks or strokes, the leading causes of death in cardiovascular disease. Current treatments for cardiovascular disease often cause excessive bleeding, while treatments for bleeding disorders can cause thrombotic disorders. To develop new therapies without these fundamental trade- offs, we need to better understand how the thrombotic process is regulated in the body.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106074-04
Application #
8585085
Study Section
Special Emphasis Panel (ZRG1-VH-E (02))
Program Officer
Link, Rebecca P
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$377,305
Indirect Cost
$76,011
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Baio, J E; Weidner, T; Interlandi, G et al. (2011) Probing Albumin Adsorption onto Calcium Phosphates by XPS and ToF-SIMS. J Vac Sci Technol B Microelectron Nanometer Struct Process Meas 29:4D113