Dr. Bergmeier Wolfgang Bergmeier, Ph.D.

Contact Dr. Bergmeier

1015 Walnut Street
Suite 702
Philadelphia, PA 19107

(215) 955-2093
(215) 923-3836 fax

Research and Clinical Interests
Dr. Bergmeier's research focuses on the adhesion mechanisms of platelets and neutrophils to sites of vascular injury/ activation. For successful adhesion, both cell types rely on activation-dependent receptors (integrins) expressed on the cell surface. We are particularly interested in the role of calcium (Ca2+) as a signaling molecule that regulates the inside-out activation of integrin receptors. Current research efforts are focused in three major areas:

1. Signaling events downstream of Ca2+. In recent studies, we were the first to identify CalDAG-GEFI as a signaling molecule critical to Ca2+-dependent integrin activation in platelets and neutrophils. Our studies further demonstrated that CalDAG-GEFI synergizes with protein kinase C (PKC) in the regulation of various aspects of platelet activation, including integrin activation and the generation of autocrine agonists such as thromboxane A2 and ADP. Consequently, mice lacking CalDAG-GEFI were characterized by a markedly impaired hemostatic and inflammatory response. We use various molecular, biochemical, and cellular strategies to better understand how CalDAG-GEFI function is regulated by Ca2+ and how it links Ca2+ to a range of responses triggered by cellular activation. We are currently also screening for small molecule inhibitors that could be used to interfere with CalDAG-GEFI function in the clinical settings of thrombosis and inflammation.

2. Molecules regulating Ca2+ influx in platelets and neutrophils. The intracellular Ca2+ concentration of many non-excitable cells is regulated by Ca2+ store release and store-operated Ca2+ entry (SOCE). We and others have recently identified STIM1 and Orai1 as critical regulators of SOCE in platelets. While STIM1 serves as a Ca2+ sensor in the endo-/sarco-plasmatic reticulum, Orai1 is the major Ca2+ channel expressed in the plasma membrane. In future studies, we hope to better understand how impaired STIM1/Orai1 function affects platelet function, especially with regard to responses regulated by CalDAG-GEFI.

3. Calcium signaling and ischemia-reperfusion injury. Myocardial Infarction (MI) and Deep Vein Thrombosis (DVT) are a national health concern, with over a million deaths per year. Reperfusion-induced tissue injury is a driving force of ischemic diseases such as MI and DVT. An important role for both leukocytes and platelets in the development of reperfusion injury has been described. We will evaluate how impaired Ca2+ signaling (CalDAG-GEFI, STIM1, Orai1) in platelets and/or neutrophils affects tissue damage in mouse models of reperfusion injury.

Publications

Most recent Peer-reviewed Publications

  1. Platelet ITAM signaling is critical for vascular integrity in infammation
  2. The Src family kinases and protein kinase C synergize to mediate G q-dependent platelet activation
  3. Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress
  4. Human genome-wide association and mouse knockout approaches identify platelet supervillin as an inhibitor of thrombus formation under shear stress
  5. Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice
  6. Extracellular matrix proteins in hemostasis and thrombosis.
  7. Extracellular matrix proteins in hemostasis and thrombosis
  8. Rap1-Rac1 circuits potentiate platelet activation
  9. Relative contributions of stromal interaction molecule 1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis
  10. CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia
  11. Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling
  12. Transfection of human platelets with short interfering RNA
  13. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model
  14. The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mi Implications for antiplatelet therapy
  15. Key role of glycoprotein Ib/V/IX and von Willebrand factor in platelet activation-dependent fibrin formation at low shear flow
  16. CalDAG-GEFI and platelet activation
  17. p38 mitogen-activated protein kinase activation during platelet storage: Consequences for platelet recovery and hemostatic function in vivo
  18. CalDAG-GEFI is at the nexus of calcium-dependent platelet activation
  19. Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion
  20. Novel molecules in calcium signaling in platelets

View All Publications