The long-term career goal of the candidate is to investigate the structural basis of hemostasis and how external factors alter it. During the K25 award he will analyze how oxidation effects alter the structure and function of two key proteins in the hemostatic process, von Willebrand Factor and fibrin. The candidate will use molecular dynamics simulations, his main expertise, to investigate how oxidation alters the structural stability of proteins. Dr. Jim Pfaendtner, an expert in accelerated molecular dynamics methods, will serve as a co-mentor. The simulations will be complemented through microscopy experiments which the candidate will learn how to perform himself under the mentorship of Dr. Wendy Thomas. Thanks to Dr. Jose Lopez as co-mentor, the candidate will gain deep knowledge of pathologies related to hemostasis. In conclusion, the candidate will learn exceptional skills outside the area of his primary expertise in order to become an essential link between clinical pathologies and structural biology. Environment. The University of Washington has a strong track record of strength in both computational protein structure analysis and in hemostasis and thrombosis research. During the transition to an independent position the candidate will be mentored by Dr. Thomas, Dr. Pfaendtner and Dr. Lopez. He will also collaborate with various other faculties like Dr. Nathan White and Dr. Xiaoyun Fu. Dr. Thomas will provide him with the necessary computational and experimental equipment and office space also after his transition to independence. The computations will be run mainly on national supercomputing resources while the experiments will be performed in the laboratory of Dr. Thomas or in the laboratories of collaborating faculties. Description. Hemostasis is an essential mechanism to prevent blood loss from a damaged vessel. It is a complicated pathway that can become out of balance and lead for example to the formation of life threatening thrombi. Inflammation leads to the production of oxidizing agents. It has been reported in the literature that oxidation alters the structure of fibrin clot and influences the function of von Wille- brand Factor. However, it is currently not understood how the molecular structure of fibrin molecules and domains of von Willebrand Factor is altered due to oxidation in order to explain the experimentally observed functional modifications. The research proposed here investigates the link between altered fibrin clot structure and structural changes in single fibrin molecules, and the altered function of von Willebrand Factor as the result of oxidation. For this purpose, a combination of molecular dynamics simulations and flow chamber experiments will be used. Understanding the function of VWF and the process of fibrin polymerization under oxidizing conditions will help the design of therapeutics that can be administered to patients who are at risk of thrombosis due to inflammation.

Public Health Relevance

The research proposed here investigates oxidation effects on two key components of hemostasis: the adhesion of von Willebrand Factor to platelets and the polymerization process of fibrin molecules during clot formation. The research will be done through a combination of flow chamber experiments and molecular dynamics simulations in the case of von Willebrand Factor and through molecular dynamics simulations under tensile force in the case of fibrin.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Quantitative Research Career Development Award (K25)
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Special Emphasis Panel (ZHL1-CSR-X (F1))
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Sarkar, Rita
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University of Washington
Biomedical Engineering
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United States
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Interlandi, Gianluca (2018) Destabilization of the von Willebrand factor A2 domain under oxidizing conditions investigated by molecular dynamics simulations. PLoS One 13:e0203675
Interlandi, Gianluca; Yakovenko, Olga; Tu, An-Yue et al. (2017) Specific electrostatic interactions between charged amino acid residues regulate binding of von Willebrand factor to blood platelets. J Biol Chem 292:18608-18617
Grant, Marianne A; Beeler, David L; Spokes, Katherine C et al. (2017) Identification of extant vertebrate Myxine glutinosa VWF: evolutionary conservation of primary hemostasis. Blood 130:2548-2558
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