Normal hemostasis is maintained by a highly regulated complex mechanism involving plasma, platelets, and endothelial cells. von Willebrand factor represents an important regulatory protein that promotes the adhesion of platelets to the vessel wall after injury and serves as a carrier protein for plasma factor VIII. Thus, von Willebrand factor serves to regulate the initial events of platelet deposition as well as the major regulatory protein, factor VIII, of the clotting process. The synthesis and multimerization of von Willebrand factor is directed by a large propolypeptide of 741 amino acids that we initially termed as von Willebrand's antigen II (vW AgII). This grant will study how natural and other mutations of the propolypeptide result in the production of mature von Willebrand factor with abnormal structure and/or function. Site-directed mutations of vW AgII will be used to determine the role of the propolypeptide in multimerization, cellular trafficking, and storage of both von Willebrand factor and FVIII. Through these studies, we expect to increase our understanding of the cellular and molecular biology of this important regulatory protein and its role in both hemorrhagic and thrombotic disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL033721-12A2
Application #
2855365
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1984-07-01
Project End
2003-03-31
Budget Start
1999-04-05
Budget End
2000-03-31
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Flood, Veronica H; Schlauderaff, Abraham C; Haberichter, Sandra L et al. (2015) Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 125:2297-304
Shi, Q; Schroeder, J A; Kuether, E L et al. (2015) The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies. J Thromb Haemost 13:1301-9
Brott, David A; Katein, Anne; Thomas, Heath et al. (2014) Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury. Toxicol Pathol 42:672-83
Kanaji, S; Fahs, S A; Ware, J et al. (2014) Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome. J Thromb Haemost 12:1726-32
Flood, Veronica H; Gill, Joan Cox; Friedman, Kenneth D et al. (2013) Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem 59:684-91
Jacobi, Paula M; Gill, Joan Cox; Flood, Veronica H et al. (2012) Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage. Blood 119:4543-53
Flood, V H; Gill, J C; Christopherson, P A et al. (2012) Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease. J Thromb Haemost 10:1425-32
Kanaji, S; Fahs, S A; Shi, Q et al. (2012) Contribution of platelet vs. endothelial VWF to platelet adhesion and hemostasis. J Thromb Haemost 10:1646-52
Kanaji, Sachiko; Kuether, Erin L; Fahs, Scot A et al. (2012) Correction of murine Bernard-Soulier syndrome by lentivirus-mediated gene therapy. Mol Ther 20:625-32
Madabhushi, Sri R; Shang, Chengwei; Dayananda, Kannayakanahalli M et al. (2012) von Willebrand factor (VWF) propeptide binding to VWF D'D3 domain attenuates platelet activation and adhesion. Blood 119:4769-78

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