This Program Project will explore the molecular basis for selected disorders of coagulation and thrombosis and the role of hemostatic balance in vascular disease pathogenesis. The individual projects in this proposal emphasize the use of new technologies to provide improved biologic insight and develop new treatments for hemorrhage, thrombosis and related cardiovascular disorders. The three individual projects contained in this PPG will: (1) continue a whole genome ENU mutagenesis analysis in the mouse to identify genetic modifiers of factor V Leiden, while also taking advantage of natural murine strain variation to identify additional thrombosis modifiers, as well as modifier genes for thrombotic thrombocytopenic purpura (TTP);(2) continue to explore the critical factors that limit factor VIII expression. The current proposal focuses on the molecular mechanisms responsible for the oxidative stress that results from misfolded FVIII in the ER lumen;and (3) explore the role of bacterial streptokinase (SK) and its interaction with plasminogen in the pathogenesis of Group A streptococcal infection;high throughput chemical screening will be used to develop specific SK inhibitors as a potential new class of antibiotics for this important human infection. The PPG will continue to support 4 cores: (A) the Mouse Coagulation Laboratory, (B) the Genetics Core, (C) the Administrative Core, and (D) the Morphology Core. The PPG will aim to increase interaction and collaboration between individual project participants, as well as among the large number of other laboratories at the University of Michigan already engaged in research on coagulation, thrombosis and vascular disease. We anticipate that the overall program resulting from the combined efforts of all participants will significantly exceed the sum of the individual parts. Relevance to public health: Abnormalities in the control of blood clotting are a critical factor in a number of diseases, including heart attack and stroke (the leadings causes of death in the US), as well as several important infectious diseases. This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment.

Public Health Relevance

to public health: Abnormalities in the control of blood clotting are a critical factor in a number of diseases, including heart attack and stroke (the leadings causes of death in the US), as well as several important infectious diseases. This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL057346-12
Application #
7802928
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1998-09-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
12
Fiscal Year
2010
Total Cost
$1,703,194
Indirect Cost
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
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Westrick, Randal J; Tomberg, Kärt; Siebert, Amy E et al. (2017) Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci. Proc Natl Acad Sci U S A 114:9659-9664
Khoriaty, Rami; Vogel, Nancy; Hoenerhoff, Mark J et al. (2017) SEC23B is required for pancreatic acinar cell function in adult mice. Mol Biol Cell 28:2146-2154
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
Xu, Xianjin; Ma, Zhiwei; Sun, Hongmin et al. (2016) SM-TF: A structural database of small molecule-transcription factor complexes. J Comput Chem 37:1559-64
Khoobchandani, Menka; Katti, Kavita; Maxwell, Adam et al. (2016) Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis. Int J Mol Sci 17:316
Tomberg, Kärt; Khoriaty, Rami; Westrick, Randal J et al. (2016) Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice. PLoS One 11:e0150852
Ji, Yan; Weng, Zhen; Fish, Philip et al. (2016) Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation. Arterioscler Thromb Vasc Biol 36:2167-2175
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
Sun, Hongmin (2015) Factor V: an active player in inflammation. Blood 126:2352-3

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