Debra K. Newman, PhD
Department of Pharmacology and Toxicology
Medical College of Wisconsin
Marquette University (1989), PhD, Immunology, Cardiovascular Pharmacology
(414) 937-3820 | Fax: (414) 937-6284
Activated platelets form thrombi at sites of blood vessel injury that are necessary to control bleeding. If not properly regulated, however, platelets can form pathological thrombi that interfere with the flow of blood to tissues, resulting in ischemia, heart attack, or stroke. To prevent or treat these conditions, it is necessary to better understand the mechanisms that regulate the platelet activation state. Platelets have both activating and inhibitory receptors that send signals into the interior of the cell. It is the balance between these signals that ultimately determines the extent of platelet activation. A major platelet activating receptor is the integrin αIIbβ3, which is required for platelets to form thrombi once they have been activated at sites of vessel injury. Studies in my laboratory are directed at identifying signaling molecules that are utilized uniquely by αIIbβ3 and not by other platelet activating receptors. Such molecules could prove useful as targets to block pathological platelet thrombus formation, while enabling sufficient platelet activation to control bleeding at sites of vessel injury. An important platelet inhibitory receptor is Platelet Endothelial Cell Adhesion Molecule (PECAM)-1, also designated CD31. PECAM-1 is an Immunoglobulin (Ig) domain and Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM)-containing inhibitory receptor that is expressed on the surfaces of platelets, leukocytes (monocytes, neutrophils and certain T-cell subsets), and endothelial cells. Studies in PECAM-1-deficient mice have revealed that, in the absence of this inhibitory receptor, platelets and leukocytes are hyper-responsive which results in an increased propensity for development of cardiovascular and inflammatory diseases, including septic shock, non-alcoholic steatohepatitis and atherosclerosis. The best-characterized mechanism by which PECAM-1 mediates its inhibitory function involves phosphorylation of its two ITIM tyrosine residues, which supports the binding and activation of an SH2 domain-containing protein tyrosine Phosphatase, SHP-2. Current studies in my laboratory are directed at defining how PECAM-1 ITIM phosphorylation is regulated. Specifically, we aim to identify and characterize the enzymes responsible for phosphorylation of each of the ITIMs and to define the events that control access of the ITIMs to the kinases that phosphorylate them. We also seek to determine whether the mechanisms that regulate PECAM-1 ITIM phosphorylate generalize to other dual ITIM-containing inhibitory receptors expressed on platelets and leukocytes. Our hope is to ultimately use this information to identify ways novel ways to control disease complications that result from platelet and leukocyte hyper-responsiveness.