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Susan C. Bock
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Phone: 801-585-6521
Office: BPRB 108D

Susan C. Bock

Professor of Medicine and of Bioengineering
Adjunct Professor of Medicinal Chemistry
Massachusetts Institute of Technology, S.B., 1975
University of California, Irvine, Ph.D., 1980
Genentech, Inc., Postdoc, 1980 - 1982

Research

Conformational Activation of Antithrombin III Anticoagulant Activity; Antithrombin III Targeting to HSPG and Heparin Surfaces


Current Research

Bock Lab research focuses on the proteinase inhibitor antithrombin III (ATIII), an essential, endogenous anticoagulant protein. There are currently 2 NIH-funded projects with structure/function/mechanism and clinical translation themes.

Conformational Change Propagation in ATIII-Heparin
The native circulating conformation of ATIIII is an inefficient proteinase inhibitor due to partial insertion of its reactive center loop in its central A beta-sheet. For full activation, cofactor heparin must bind and induce a protein conformational change that leads to reactive loop expulsion and a ~300x increase in the fXa inhibition rate. The goals of this project are to identify ATIII structural elements and interactions that mediate conformational change transmission across the ~35 Ĺ distance between the pentasaccharide-binding site and the reactive center loop. A model for ATIII heparin-dependent conformational change propagation was proposed and is being evaluated and refined by disrupting hypothesized, critical structural interactions, and determining how the introduced changes affect heparin binding kinetics and affinities, allosteric activation of fXa inhibition, and the molecular structures of the mutants.

ATIII Targeting to Vascular and Biomaterial Surfaces
Activation of thrombin and fXa occurs on vascular and biomaterial surfaces and initiates coagulation, platelet, signaling and cell proliferation reactions, which may subsequently promote pathological thrombosis, occlusion and restenosis in the native circulatory system and on surfaces of implanted biomaterials and medical devices. Early intervention via the neutralization of thrombin and fXa molecules as they are generated at blood – surface interfaces would be a widely applicable strategy for reducing thrombin/fXa mediated pathologies. Implementation of this approach will require blood-borne inhibitors that target vascular and biomaterial surfaces and remain stable under focal and systemic inflammatory conditions. We have developed candidate “super-beta ATIIIs” that inhibit thrombin and fXa with comparable efficiency to plasma-derived ATIII, but bind the pentasaccharide sequence of heparin and vascular wall heparan sulfate proteoglycans (HSPGs) with 50x greater affinity. Under flow conditions, the recombinants also load onto heparin-coated surfaces up to 7x more efficiently than does plasma ATIII, and are 10x more resistant to cleavage and inactivation by neutrophil elastase. The targeted ATIII project will investigate how mass transport and heparin binding affinity factors influence ATIII surface delivery under low-vs-high wall shear rate & steady-vs-pulsatile flow conditions, using in vitro flow model measurements and mathematical simulations. We will also evaluate super-beta-ATIII performance in vivo, using rabbit extracorporeal shunt and carotid stenosis models of thrombosis.