Protease-activated receptors (PARs) were discovered in the context of an effort to understand how thrombin and other proteases regulate cellular behaviors. Four PARs are found in mammals. PARs 1,3, and 4 are thrombin receptors that mediate activation of platelets and other cells by thrombin and play key roles in hemostasis and perhaps inflammatory and other responses to tissue injury. By contrast, physiological activators of PAR2 have not been clearly identified, and its roles in vivo are uncertain. Our recent work suggests that PARs play roles in contexts other than response to injury. PAR1 function in endothelial cells is important for proper vascular development, and we now find that PAR2 also plays distinctive roles in the embryo. In one strain background, Par2-/- embryos develop profound anemia. Moreover, Par1 -/-Par2 -/- embryos show a strong phenotype not seen in either single knockout: exencephaly, a hallmark of failed neural tube closure. PAR2 is expressed in the epidermal ectoderm overlying the neuroepithelium before and during neural tube closure, that is, at the right place and time to play a direct role. We will better define these interesting phenotypes and identify the exact cell types involved by transgene rescue and cell type-specific knockout. What does PAR2 regulate and what does it sense in these contexts? We have developed mouse lines that will be used to ablate specific G protein signaling pathways in the cell types in which PAR2 function is important for development. Phenocopies of PAR-deficiencies will help identify which of the several G proteins regulated by PARs is important for the phenotypes described above, and novel phenotypes will point to new roles for G protein-coupled receptors in embryonic development. We also plan systematic candidate-driven approach to identify PAR2-activating proteases that might function in the embryo. These studies will provide new insights into basic mechanisms underlying hematopoiesis, vascular development and/or neurulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL044907-15
Application #
6926813
Study Section
Special Emphasis Panel (ZRG1-HEME-C (03))
Program Officer
Ganguly, Pankaj
Project Start
1991-04-01
Project End
2009-03-31
Budget Start
2005-04-22
Budget End
2006-03-31
Support Year
15
Fiscal Year
2005
Total Cost
$431,192
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bynagari-Settipalli, Yamini S; Cornelissen, Ivo; Palmer, Daniel et al. (2014) Redundancy and interaction of thrombin- and collagen-mediated platelet activation in tail bleeding and carotid thrombosis in mice. Arterioscler Thromb Vasc Biol 34:2563-9
Zhang, Cheng; Srinivasan, Yoga; Arlow, Daniel H et al. (2012) High-resolution crystal structure of human protease-activated receptor 1. Nature 492:387-92
Green, Jesse A; Suzuki, Kazuhiro; Cho, Bryan et al. (2011) The sphingosine 1-phosphate receptor S1P? maintains the homeostasis of germinal center B cells and promotes niche confinement. Nat Immunol 12:672-80
Shao, Bojing; Wahrenbrock, Mark G; Yao, Longbiao et al. (2011) Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 118:4015-23
Cornelissen, Ivo; Palmer, Daniel; David, Tovo et al. (2010) Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. Proc Natl Acad Sci U S A 107:18605-10
Camerer, Eric; Barker, Adrian; Duong, Daniel N et al. (2010) Local protease signaling contributes to neural tube closure in the mouse embryo. Dev Cell 18:25-38
Hamilton, J R; Cornelissen, I; Mountford, J K et al. (2009) Atherosclerosis proceeds independently of thrombin-induced platelet activation in ApoE-/- mice. Atherosclerosis 205:427-32
Regard, Jean B; Sato, Isaac T; Coughlin, Shaun R (2008) Anatomical profiling of G protein-coupled receptor expression. Cell 135:561-71
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
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

Showing the most recent 10 out of 70 publications