The objective this proposal is the delineation of novel pathogenic mechanisms underlying adverse pregnancy outcome associated with thrombophilia. Our work in the context of the parent proposal to study the function of the blood clotting regulator thrombomodulin (TM) has shown that the loss of TM function causes intrauterine fetal loss. We found that the developmental failure of TM-null mice is secondary to a defect in fetal trophoblast cells of the placenta. Contrary to the current concept of the pathogenic mechanism underlying the association of thrombophilia and adverse pregnancy outcome, the intrauterine death of TM-deficient embryos is not caused by thrombosis of placental blood vessels, but rather is due to the death of fetal trophoblast cells caused by fibrin degradation products, and a concomitant arrest of placental growth that is likely caused by inadvertent engagement of protease activated receptors (PAR's) for coagulation factors. Here, we wish to delineate the molecular mechanism underlying the fatal defects in fetal placental trophoblast of TM-deficient embryos and test the hypothesis that thrombophilia of the mother causes fetal loss through similar mechanism as those delineated in TM-deficient mice. To this end, we propose to (1) characterize the ligand, the receptor, and the intracellular apoptotic pathways mediating cell death induced by fibrin degradation products, (2) delineate the role of receptors for coagulation factors in the development and function of the placenta, and (3) establish a mouse model of fetal loss caused by thrombophilia of the mother that will enable investigations into the underlying pathogenesis. Results from these specific aims should provide potentially novel insights into the structural and functional basis of a previously unknown pathway regulating cell survival of placental trophoblast cells, test the working hypothesis that protease receptor engagement by coagulation factors regulates placental growth, and address the pathogenic mechanism underlying fetal loss experienced by mothers with underlying thrombophilic states, such as that caused by the factor V Leiden mutation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060655-09
Application #
7215197
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
1999-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2007
Total Cost
$359,140
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
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Sood, Rashmi; Sholl, Lynette; Isermann, Berend et al. (2008) Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin. Blood 112:585-91
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Sood, Rashmi; Zogg, Mark; Westrick, Randal J et al. (2007) Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers. J Exp Med 204:1049-56
Sood, Rashmi; Kalloway, Shawn; Mast, Alan E et al. (2006) Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells. Blood 107:3173-80
Miano, Joseph M; Ramanan, Narendrakumar; Georger, Mary A et al. (2004) Restricted inactivation of serum response factor to the cardiovascular system. Proc Natl Acad Sci U S A 101:17132-7
Kerlin, Bryce; Cooley, Brian C; Isermann, Berend H et al. (2004) Cause-effect relation between hyperfibrinogenemia and vascular disease. Blood 103:1728-34

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