von Willebrand factor (VWF) is a key component of the blood coagulation system. Deficiencies of VWF result in the most common inherited bleeding disorder in humans, von Willebrand disease (VWD). In contrast, elevated levels of VWF and the associated protein, factor VIII, are a major risk factor for thrombosis. This is an application for competing renewal of a research program focused on the molecular genetics of VWF. Considerable progress was made over the last funding cycle, including the identification of multiple genetic factors regulating the plasma level of VWF in laboratory mice and in humans. In addition, the genes for 2 related disorders of VWF and FVIII were identified: ADAMTS13 as the cause of familial thrombotic thrombocytopenic purpura (TTP) and MCFD2/LMAN1 as the cause of combined deficiency for factors V and VIII. The current proposal will continue and extend the body of work from the previous funding cycle. The 8 genetic loci that were previously identified to contribute to variability in plasma VWF levels among inbred mouse strains (Mvwf1-8) will be further characterized at the molecular level. Building on initial preliminary studies, direct genetic analysis for human modifiers of VWF and other hemostatic factors will be conducted using a cohort of 1182 healthy young subjects collected at the University of Michigan. In addition, a new approach will be undertaken to extend this genetic strategy to identify potential genetic modifiers of VWF levels in a zebrafish model system. The genetic power of the mouse and zebrafish systems may facilitate the identification of the critical genes modifying plasma VWF levels in humans, as well as yielding information about fundamental VWF biology that could lay the ground work for novel approaches to diagnosis and treatment in the future. Finally, the application of new high throughput sequencing technologies to a modified phage display strategy will be used to finely map functional domains within the VWF protein and to select for novel recombinant proteins with potential therapeutic utility.

Public Health Relevance

The studies proposed in this application will advance understanding of the molecular and genetic basis for decreased von Willebrand factor levels that result in bleeding in von Willebrand disease and elevated VWF levels associated with many cases of abnormal blood clotting (thrombosis). These findings should lead to improved diagnosis for both inherited bleeding and blood clotting diseases and facilitate more tailored selection of therapy in individual patients. These studies may also lay the groundwork for the development of new therapies in the future to treat both common bleeding and blood clotting diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039693-23
Application #
8434213
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
1988-12-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
23
Fiscal Year
2013
Total Cost
$382,541
Indirect Cost
$114,596
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Khoriaty, Rami; Everett, Lesley; Chase, Jennifer et al. (2016) Pancreatic SEC23B deficiency is sufficient to explain the perinatal lethality of germline SEC23B deficiency in mice. Sci Rep 6:27802
Emmer, Brian T; Ginsburg, David; Desch, Karl C (2016) Von Willebrand Factor and ADAMTS13: Too Much or Too Little of a Good Thing? Arterioscler Thromb Vasc Biol 36:2281-2282
Ozel, A B; McGee, B; Siemieniak, D et al. (2016) Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance. J Thromb Haemost 14:1888-98
Machiela, Mitchell J; Zhou, Weiyin; Sampson, Joshua N et al. (2015) Characterization of large structural genetic mosaicism in human autosomes. Am J Hum Genet 96:487-97
Yee, Andrew; Oleskie, Austin N; Dosey, Anne M et al. (2015) Visualization of an N-terminal fragment of von Willebrand factor in complex with factor VIII. Blood 126:939-42
Kretz, Colin A; Dai, Manhong; Soylemez, Onuralp et al. (2015) Massively parallel enzyme kinetics reveals the substrate recognition landscape of the metalloprotease ADAMTS13. Proc Natl Acad Sci U S A 112:9328-33
Desch, Karl C; Kretz, Colin; Yee, Andrew et al. (2015) Probing ADAMTS13 substrate specificity using phage display. PLoS One 10:e0122931
Desch, Karl C (2015) Dissecting the genetic determinants of hemostasis and thrombosis. Curr Opin Hematol 22:428-36
Adams, Elizabeth J; Chen, Xiao-Wei; O'Shea, K Sue et al. (2014) Mammalian COPII coat component SEC24C is required for embryonic development in mice. J Biol Chem 289:20858-70
Everett, Lesley A; Cleuren, Audrey C A; Khoriaty, Rami N et al. (2014) Murine coagulation factor VIII is synthesized in endothelial cells. Blood 123:3697-705

Showing the most recent 10 out of 60 publications