The hemostatic balance is regulated by vascular bed-specific endothelial cell signaling pathways. We propose that coronary artery thrombosis arises through local alternations in one or more of these pathways. The overall goal of the Collaborative Program are to elucidate the molecular basis of endothelial cell subtype-specific gene expression in the hear and to identify the critical components of cardiac hemostasis. 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. Dr. Aird will examine the role of the Egr-1 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. 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 monocyte-derived TF to cardiac hemostasis. 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. Dr. Rosenberg provides expertise in both genetic mouse models of hyper- coagulability and in the functional analysis of in vivo hemostasis. Dr. Aird contributes tools for studying vascular bed-specific gene regulation. Dr. Mackman has experience in studying TF gene regulation in cultured cells and animal models. Dr. Housman is an acknowledged expert in human genomics. Taken together, the individual projects and the collaborative efforts promise to provide important insight into the molecular basis of cardiac hemostasis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065226-01
Application #
6153469
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M1))
Program Officer
Jacobs, Tom P
Project Start
2000-08-01
Project End
2005-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$354,600
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Talluri, Rajesh; Shete, Sanjay (2018) An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose. Ann Hum Genet 82:396-406
Wang, Jian; Shete, Sanjay (2018) Estimation of indirect effect when the mediator is a censored variable. Stat Methods Med Res 27:3010-3025
Raffield, Laura M; Ellis, Jaclyn; Olson, Nels C et al. (2018) Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study. J Hum Genet 63:327-337
Kulminski, Alexander M; Huang, Jian; Loika, Yury et al. (2018) Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. Aging (Albany NY) 10:492-514
Leary, Peter J; Kronmal, Richard A; Bluemke, David A et al. (2018) Histamine H2 Receptor Polymorphisms, Myocardial Transcripts, and Heart Failure (from the Multi-Ethnic Study of Atherosclerosis and Beta-Blocker Effect on Remodeling and Gene Expression Trial). Am J Cardiol 121:256-261
He, Liang; Culminskaya, Irina; Loika, Yury et al. (2018) Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study. Exp Gerontol 107:74-86
Bray, Michael J; Wellons, Melissa F; Jones, Sarah H et al. (2018) Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women. Fertil Steril 110:737-745.e34
Keaton, Jacob M; Gao, Chuan; Guan, Meijian et al. (2018) Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans. Genet Epidemiol 42:559-570
Weng, Lu-Chen; Guan, Weihua; Steffen, Lyn M et al. (2018) Pleiotropic effects of n-6 and n-3 fatty acid-related genetic variants on circulating hemostatic variables. Thromb Res 168:53-59
Chen, Guanjie; Doumatey, Ayo P; Zhou, Jie et al. (2017) Genome-wide analysis identifies an african-specific variant in SEMA4D associated with body mass index. Obesity (Silver Spring) 25:794-800

Showing the most recent 10 out of 79 publications