Polyphosphate modulates hemostasis, thrombosis, and inflammation

Polyphosphate (polyP) is a linear polymer of inorganic phosphates that is secreted by activated platelets and is abundant in many pathogenic microorganisms. Our lab has recently shown that polyP from bacteria and human platelets play important roles in inflammation and coagulation in vitro and in vivo, supporting the paradigm of polyP as the long-sought (patho)physiologic activator of the contact pathway of blood clotting. These studies also implicate polyP in contributing to thrombosis and consumptive coagulopathies accompanying bacterial sepsis. PolyP polymer lengths are known to vary substantially among different organisms and cell types, with shorter polymers secreted by human platelets and much longer polymers accumulating in microorganisms, raising intriguing questions about the mechanisms by which various polyP sizes differentially modulate the blood clotting system. To accomplish this goal, I used bacterial and platelet-derived polyP, in addition to carefully size-fractionated synthetic polyP preparations, to investigate how polyP (dependent on polymer size) promotes each of the individual enzyme reactions that result in triggering and propagating blood clotting reactions. This data advances our understanding of the mechanisms by which polyP modulates blood clotting and inflammation, with a particular emphasis on the contact pathway and factor V activation. A serious impediment to progress in studying polyP in biological systems is the dearth of techniques for manipulating polyP to investigate polyP-protein interactions. To this end, I developed a novel method for covalently crosslinking polyP to solid supports or labeling polyP with primary amine-containing solid supports. This technique of crosslinking polyP has already facilitated studies on the ever-expanding role of polyP in blood clotting and other important biological processes.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Choi, Sharon

Contributors dc:contributor

• Morrissey, James H.
• Tapping, Richard I.
• Tajkhorshid, Emad
• Fratti, Rutilio A.

• blood
• coagulation
• thrombosis
• polyphosphate

Statement dc:rights

• Copyright 2012 Sharon Choi

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/42451

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/42451