Disabled-2 regulates platelet heterotypic and homotypic aggregation through sulfatide binding

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dc.contributor.authorWelsh, John Douglasen
dc.contributor.committeechairFinkielstein, Carla V.en
dc.contributor.committeememberHuckle, William R.en
dc.contributor.committeememberCapelluto, Daniel G. S.en
dc.contributor.departmentBiologyen
dc.date.accessioned2014-03-14T20:33:24Zen
dc.date.adate2010-05-14en
dc.date.available2014-03-14T20:33:24Zen
dc.date.issued2010-03-29en
dc.date.rdate2013-05-21en
dc.date.sdate2010-04-12en
dc.description.abstractAt the site of vascular injury platelet aggregation serves to stem blood flow, initiate the inflammatory response, and stimulate wound healing. Platelets become stimulated, release their granule contents, and become adherent to one another. Platelet granules contain important clotting factors and regulators of aggregation. Disabled-2 (Dab2) is a negative regulator of platelet aggregation released from platelet α-granules. Dab2 binds to the αIIbβ3 integrin, through the PTB domain, and blocks fibrin binding to the integrin which serves as the major cause of platelet-platelet interactions. Dab2 is also capable of binding to sulfatides, through the N-PTB region, expressed on the outer leaflet of adjacent cells. Dab2-sulfatide binding decreases Dab2's ability to interact with the αIIbβ3 integrin, however sulfatides activate and stimulate platelet-platelet and platelet-leukocyte aggregation. Sulfatide addition to platelets stimulates increased αIIbβ3 integrin and P-selectin expression through stimulation of continued platelet degranulation, and these surface receptors mediate platelet heterotypic and homotypic aggregation. Here, we show that Dab2 N-PTB binding of sulfatides serves to increase the inhibitory affect of Dab2. Sulfatide stimulation of platelet degranulation can be blocked by the addition of N-PTB. Inhibition of sulfatide induced αIIbβ3 integrin and P-selectin expression result in decreased platelet-platelet aggregation under flow. N-PTB also blocks sulfatide induced platelet-leukocyte interactions and aggregation. Experimental data supports the hypothesis that Dab2-sulfatide binding serves to increase the inhibition of platelet aggregation.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-04122010-093714en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-04122010-093714/en
dc.identifier.urihttp://hdl.handle.net/10919/31695en
dc.publisherVirginia Techen
dc.relation.haspartWelsh_JD_T_2010.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectleukocytesen
dc.subjectplateletsen
dc.subjectsulfatidesen
dc.subjectDisabled-2en
dc.titleDisabled-2 regulates platelet heterotypic and homotypic aggregation through sulfatide bindingen
dc.typeThesisen
thesis.degree.disciplineBiologyen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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