This research will be done primarily at Institute of Biophysics, Chinese Academy of Sciences in Beijing, China in collaboration with Professor Jizhong Lou as an extension of NIH grant R01 HL093723- 01A1. This FIRCA application has a due objective: 1) to expand and enhance the parent grant and 2) to increase the research capacity of Dr. Jizhong Lou's group. The goal of this and the parent proposal is to elucidate the mechanical regulation of molecular interactions between von Willebrand factor and ADAMTS- 13, which are key interactions on physiological hemostasis and pathological thrombosis. Malfunction in the interactions may lead to von Willebrand disease and thrombotic thrombocytopenic purpura. ADAMTS- 13/VWF interaction are regulated mechanically as they take place in the hydrodynamic environment of the circulation. Our hypothesis for this FIRCA grant is that hydrodynamic forces induce the unfolding of VWF A2 domain which promote its interactions to ADAMTS-13, the binding with ADAMTS-13 will also lead to the conformational changes on ADAMTS-13 for efficient proteolysis and the conformations are regulated by the degree of A2 unfolding and mechanical forces. The broad hypothesis will be tested in two specific aims: 1) Elucidate the structural mechanisms of type 2A VWD by comparing the force- and thermo-induced unfolding pathways of wild-type (WT) VWF A2 domain and a panel of mutant VWF A2 domains, and 2) 2.Develop atomic models for the ADAMTS-13/A2 interactions and determine how these interactions regulate A2 unfolding and ADAMTS-13 conformational changes.
These specific aims are computational studies, which complement the parent grant. The molecular dynamics simulations and molecular modeling proposed in the FIRCA grant will help to interpret the experimental data obtained from the parent grant and provide opportunities to design new experiments to test the overall hypothesis of the parent and the FIRCA grant. Decoding how mechanical forces regulate VWF A2 unfolding, ADAMTS-13 conformations and the interactions between the two molecules will provide key insights into vascular physiology and pathology. As a result, the data may office new therapeutic approaches to relevant diseases.
This FIRCA proposal extends the parent grant in several ways. Information obtained from the parent and this FIRCA grants will help develop new therapeutic approaches to type 2A von Willebrand disease and thrombotic thrombocytopenic purpura.
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|Zhu, Cheng (2014) Mechanochemitry: a molecular biomechanics view of mechanosensing. Ann Biomed Eng 42:388-404|