In this three-year fellowship, I plan to define the role of heparin in the modulation of the human platelet integrin. Our principal hypothesis is that heparin binds to the platelet integrin receptor GplIblIIa ((IIb(3), and alters its function. Using recombinant protein expression and functional assays with human platelets, as well as the model system of K562 cells expressing that integrin, I propose to define which integrin subunits are modulated by heparin and whether heparin's action depends exclusively on either subunit. Secondly, I plan to define the mechanisms by which heparin modulates integrin function, by examining receptor conformation and signaling. The laboratories of Dr. Sobel and the Vascular Biology Group at the University of Washington will provide excellent resources and environment to accomplish these goals. My mentoring committee includes leaders in each of the specific scientific fields where I will be acquiring new scientific skills. The experiments in the Aims should clearly show if our hypothesis is correct, and will define the precise structure-function relations and signaling pathways of heparin's interactions with the platelet integrin alphaIIb/beta3. Additional experiments are also anticipated to point to alternative hypotheses if our initial ones are not borne out.
