Our research focuses on the molecular mechanisms by which platelets contribute to health and disease, i.e. to physiological and pathological situations such as hemostasis and thrombosis, vascular integrity, angiogenesis, tumor metastasis and cancer growth, and inflammation. A particular focus is on integrin-mediated adhesion of platelets to sites of vascular injury/ activation, and on 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. 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. Key technologies include NMR spectroscopy, proteomics/ mass spectrometry, viral-based complementation strategy in bone marrow cells, rheology studies using microfluidics chambers, and intravital microscopy. 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. Platelets in Health and Disease

Ongoing studies aim at a better understanding of the molecular mechanisms by which platelets contribute to the following physiological and pathological processes: Hemostasis and thrombosis, heparin-induced thrombocytopenia and thrombosis (HIT), idiopathic thrombocytopenia purpura (ITP), reperfusion injury (myocardial infarction deep vein thrombosis), atherosclerosis, and vascular integrity during inflammation.