Beth Israel Deaconess Medical Center 330 Brookline Ave; CLS-0604
Boston, MA 02215
Advanced Degree And Training Info:
Year
Institution
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Research Team Listing
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Areas of Interest:
Cancer & Hematologic
Cardiovascular
Genetics / Genomics
Gerontology / Aging
Immunology, Transplantation
Infectious Diseases, Inflammation
Informatics / Bioinformatics
Metabolic / Metabolic Diseases
Vascular Biology
Major Research Theme:
Extracellular nucleotides (e.g. ATP, ADP, UTP, UDP) are released by many types of cells including erythrocytes, leukocytes, platelets and endothelium. These nucleotides appear to provide poorly characterized, yet ubiquitous, environmental signals or cues within the vasculature and other organs. These mediators bind type-2 purinergic/pyrimidinergic (P2Y and P2X) receptors on cell surface and transmit signals that trigger and modulate cellular metabolism, nitric oxide (NO) release, adhesion, activation, proliferation and apoptosis. Nucleotide-mediated effects are regulated by ectonucleotidases (ecto-ADPases, ecto-ATPases etc.) that hydrolyze extracellular nucleotides, ultimately to the respective nucleosides (that in turn activate series of adenosine receptors).
We have shown that CD39/nucleoside triphosphate diphosphohydrolase-1(NTPDase1) is the dominant ectonucleotidase expressed by vascular endothelial cells (EC) and vascular smooth muscle cells (VSMC) and created the mutant mice deficient in cd39/NTPDase1.
NTPDase1 hydrolyses both tri- and diphosphonucleosides and blocks platelet aggregation responses to ADP. Global deletion of NTPDase1 in mice results in major perturbations of P2-receptor mediated signaling in the vasculature. This phenomenon manifests as hemostatic defects, thromboregulatory disturbances, systemic hypertension and abnormalities in angiogenesis. This mutant mice, despite heightened acute inflammatory responses, fail to generate chronic inflammatory lesions. These phenomena have been ascribed to differential P2-receptor desensitization and consequent integrin dysfunction.
It has been reported that extracellular nucleotides are able to modulate metabolic pathway not only inflammation nor coagulation. We are therefore currently working on this knockout mice to elucidate the role of extracellular nucleotides in the development of metabolic syndrome including atherosclerosis.
Enjyoji, Sevigny, Lin, Frenette, Christie, Esch, Imai, Edelberg, Rayburn, Lech, Beeler, Csizmadia, Wagner, Robson and Rosenberg: Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med 5: 1010-1017, 1999.
Mizumoto, Kumamoto, Robson, Sevigny, Matsue, Enjyoji and Takashima: CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat Med 8: 358-365, 2002.
Robson, Wu, Sun, Knosalla, Dwyer and Enjyoji: Ectonucleotidases of CD39 family modulate vascular inflammation and thrombosis in transplantation. Semin Thromb Hemost 31: 217-233, 2005.
Enjyoji, Kotani, Thukral, Blumel, Sun, Wu, Imai, Friedman, Csizmadia, Bleibel, Kahnand Robson. Deletion of Cd39/Entpd1 results in hepatic insulin resistance. Diabetes in press.
