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 #
5P01HL057346-15
Application #
8450233
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
2013-04-01
Budget End
2014-03-31
Support Year
15
Fiscal Year
2013
Total Cost
$1,545,591
Indirect Cost
$384,014
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
Cao, Stewart Siyan; Kaufman, Randal J (2014) Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 21:396-413
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
Ferris, Sean P; Kodali, Vamsi K; Kaufman, Randal J (2014) Glycoprotein folding and quality-control mechanisms in protein-folding diseases. Dis Model Mech 7:331-41
Han, Jaeseok; Kaufman, Randal J (2014) Measurement of the unfolded protein response to investigate its role in adipogenesis and obesity. Methods Enzymol 538:135-50
Groenendyk, Jody; Peng, Zhenling; Dudek, Elzbieta et al. (2014) Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis. Sci Signal 7:ra54
Wang, Shiyu; Kaufman, Randal J (2014) How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver? Curr Opin Lipidol 25:125-32
Ji, Y; Fish, P M; Strawn, T L et al. (2014) C-reactive protein induces expression of tissue factor and plasminogen activator inhibitor-1 and promotes fibrin accumulation in vein grafts. J Thromb Haemost 12:1667-77
Cao, Stewart S; Wang, Miao; Harrington, Jane C et al. (2014) Phosphorylation of eIF2? is dispensable for differentiation but required at a posttranscriptional level for paneth cell function and intestinal homeostasis in mice. Inflamm Bowel Dis 20:712-22
Khoriaty, Rami; Vasievich, Matthew P; Jones, Morgan et al. (2014) Absence of a red blood cell phenotype in mice with hematopoietic deficiency of SEC23B. Mol Cell Biol 34:3721-34

Showing the most recent 10 out of 143 publications