Abnormalities in the regulation of coagulation and thrombosis play a major role in the pathogenesis of many heart, lung, and blood diseases. This Program Project will integrate the research efforts of a number of independent investigators to explore the molecular basis for selected disorders of coagulation and thrombosis and the role of hemostatic balance in vascular disease pathogenesis. The PPG builds on the existing strength at the University of Michigan in human molecular genetics and cell and molecular biology of blood coagulation. 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 four individual projects contained in this PPG will: 1) employ a whole genome ENU mutagenesis scan in an effort to identify a large panel of modifier genes for factor V Leiden in the mouse as candidate genes contributing to thrombosis susceptibility in humans with factor V Leiden and other prothrombotic disorders; 2) explore the role of ER processing in coagulation FV and FVIII biosynthesis to identify the molecular basis for combined deficiency of factor V and factor VIII, and examine the role of altered FVIII level as a risk factor for thrombosis; 3) and 4) study the contribution of the fibrinolytic system components PAI1 and vitronectin to the pathogenesis of atherosclerosis (3) and the pathologic response to vascular injury leading to neointimal hyperplasia (4), and the potential of this system as a target for therapeutic intervention. The PPG will support the development of 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL057346-09
Application #
7103495
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1997-09-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
9
Fiscal Year
2006
Total Cost
$1,800,950
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
Tomberg, Kärt; Westrick, Randal J; Kotnik, Emilee N et al. (2018) Whole exome sequencing of ENU-induced thrombosis modifier mutations in the mouse. PLoS Genet 14:e1007658
Khoriaty, Rami; Hesketh, Geoffrey G; Bernard, Amélie et al. (2018) Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo. Proc Natl Acad Sci U S A 115:E7748-E7757
Nie, Chao; Wang, Huimin; Wang, Rui et al. (2018) Dimeric sorting code for concentrative cargo selection by the COPII coat. Proc Natl Acad Sci U S A 115:E3155-E3162
Ji, Y; Adeola, O; Strawn, T L et al. (2017) Recombinant soluble apyrase APT102 inhibits thrombosis and intimal hyperplasia in vein grafts without adversely affecting hemostasis or re-endothelialization. J Thromb Haemost 15:814-825
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
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
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
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
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

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