Description of CVI Expertise

CVI Program Unit(s):
Thrombosis / Hemostasis

CVI Research Description:
ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) is a reprolysin-like metalloprotease that limits platelet aggregation by cleaving the Tyr1605-Met1606 bond of von Willebrand factor (VWF). Deficiency of plasma ADAMTS13 results in an accumulation of “unusually large” VWF multimers released from endothelial cells, leading to spontaneous platelet aggregation and subsequent thrombosis in small arteries. This pathological feature is found in thrombotic thrombocytopenic purpura (TTP). We have determined the domain structure of ADAMTS13. It consists of a propeptide, a metalloprotease domain, a disintegrin domain and first thrombospondin type 1 repeat (TSP1), followed by a Cys-rich domain and a spacer domain. The carboxyl terminus of ADAMTS13 has additional seven TSP1 repeats and two CUB domains. The role of these carboxyl terminal domains in substrate recognition is not fully understood.

My lab is interested in understanding: 1) the domains of ADAMTS13 required for recognition of VWF substrate on cells and in solution; 2) cofactor-dependent regulation of ADAMTS13 function; 3) characterization of anti-ADAMTS13 autoantibodies in patients with acquired TTP; 4)development of vector and cell-based gene transfer strategies for correction of ADAMTS13 deficiency and TTP in a mouse model. Recombinant DNA, protein engineering, expression and purification, cell culture, immunofluorescent, confocal and electron microscopies, and various other biochemical and biophysical assays will be employed in the laboratory. The advances in this area will not only shed more light on understanding of the pathogenesis of TTP, but also provide novel tools for diagnosis and cure of TTP and other related thrombotic disorders.