The hemostatic balance is regulated by vascular bed-specific endothelial cell signaling pathways. The applicants propose that coronary artery thrombosis arises through local alterations in one or more of these pathways. The overall goals of the Collaborative Program are to elucidate the molecular basis of endothelial cell subtype-specific gene expression in the heart and to identify the critical components of cardiac hemostasis. In this project , Dr. Rosenberg will study the role of a platelet-derived growth factor signaling pathway in mediating expression of a gene program within cardiac microvascular endothelial cells that includes tissue factor (TF). He will also optimize a recently developed mouse model of coronary artery thrombosis. In this project, Dr. Aird will examine the role of the Egr-l transcription factor in mediating cardiac-specific hemostasis. He will ask how a single gene can serve to """"""""fine tune"""""""" hemostasis according to the local needs of the tissue. In this project, Dr. Mackman will evaluate the role of a thrombin-PAR-1 signaling pathway in governing local levels of procoagulant (TF) and fibrinolytic (tissue-type plasminogen activator) molecules within the heart. In addition, he will address the contribution of monocytederived TF to cardiac hemostasis. In this project, Dr. Housman will use genetic approaches in large populations to identify genotypes which significantly contribute to coronary thrombosis. The three basic science projects are interrelated by several common themes. Each component involves: (1) the study of a cardiac endothelial cell type-specific signaling pathway, (2) the determination of the effects of cell type-specific signaling pathways on global hemostasis (fibrin deposition) (3) the study of TF gene regulation and its role as the initiator of coagulation in the cardiac circulation, and (4) the use of transgenic mouse technology for studying vascular-bed specific hemostasis in the heart. The clinical project will serve as a vital link to validate the role of local hemostatic components in human populations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065230-02
Application #
6390808
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M1))
Program Officer
Ganguly, Pankaj
Project Start
2000-09-01
Project End
2005-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$312,660
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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