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. Rap1-rac1 circuits potentiate platelet activation
  2. Relative contributions of stromal interaction molecule 1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis
  3. CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia
  4. Transfection of human platelets with short interfering RNA
  5. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model
  6. The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: Implications for antiplatelet therapy
  7. Key role of glycoprotein Ib/V/IX and von Willebrand factor in platelet activation-dependent fibrin formation at low shear flow
  8. CalDAG-GEFI and platelet activation
  9. p38 mitogen-activated protein kinase activation during platelet storage: Consequences for platelet recovery and hemostatic function in vivo
  10. Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion.
  11. CalDAG-GEFI is at the nexus of calcium-dependent platelet activation.
  12. Novel molecules in calcium signaling in platelets
  13. R93W mutation in Orai1 causes impaired calcium influx in platelets
  14. CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin αIIbβ3 in platelets
  15. Thrombocytopenia and platelet abnormalities in high-density lipoprotein receptor-deficient mice.
  16. Glycoprotein Ibα and von Willebrand factor in primary platelet adhesion and thrombus formation: Lessons from mutant mice
  17. PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets
  18. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III
  19. Von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins
  20. In vitro function and phagocytosis of galactosylated platelet concentrates after long-term refrigeration

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