Description of CVI Expertise

CVI Program Unit Administrator:
Thrombosis / Hemostasis

Research Interests
mechanisms of thrombosis

Key Words: vascular biology, thrombosis, atherosclerosis, signal transduction, platelets, endothelial cells, G protein coupled receptors, integrins, tyrosine kinases, Ras family members.

Description of Research
The studies in my laboratory focus on the molecular basis for platelet activation. Despite major medical advances over the past 20 years, atherosclerotic cardiovascular disease and vascular thrombosis remain among the major causes of death and chronic illness in the United States. Inappropriate platelet activation is clearly a contributor to that problem, which is why millions of dollars are spent every year in the development and clinical application of drugs designed to inhibit platelet function. The work we are doing focuses on human platelet biology, but makes considerable use of transgenic and knockout mouse models as well. Topics that we currently have under investigation and that will provide appropriate topics for lab rotations and thesis projects include:

1. The role of the Gi family members, including Gz, in platelet activation. G proteins are molecular switches that activate or retard the intracellular events that regulate cell function. Although most G proteins are expressed in most tissues, a few are expressed only in a limited number of tissues. Gz is one of the G proteins that are not universally expressed, its presence being limited mainly to some neural cells and to some hematopoietic cells, particularly megakaryocytes and platelets. We have recently completed the development of mice that lack the a subunit of Gz and have on hand mice that lack Gi2, Gi3 and Gq. The Gz mice have a disorder of platelet function that is able to protect them from the mortality and morbidity in acute thrombosis models. We are using all of the mice to map pathways that are involved in platelet activation. One such pathway leads to the activation of Ras family member, Rap1b, in platelets, and from there to integrin activation.

2. The consequences of dysregulation of platelet activation. We have recently been funded to develop mouse models of platelet hyper-reactivity to see if this increases the predisposition of the mice to arterial thrombosis and the development of arteriosclerosis. Our general approach has been to create transgenic mice in which constitutively active G protein a subunits are predicted to lead to overly-active platelets.

3. Mechanisms of contact-dependent signaling in platelets, including Eph kinases and the cell adhesion molecule, L1-CAM.. Eph receptors are a large family of membrane-bound tyrosine kinases whose function is largely unknown. Recent studies have shown that interactions between Eph receptors and their ligands play an important role in the developing central nervous system. Nick Prevost, a graduate student in my lab, has recently shown for the first time that these proteins are expressed in human platelets and has provided convincing evidence that these receptors and their ligands form signaling complexes that play a role in the formation of stable platelet aggregates. Components of these signaling complexes include non-receptor tyrosine kinases, adaptor proteins and cell adhesion molecules.

Rotation Projects for 2006-2007
At any given time there are a number of projects that are suitable for a lab rotation. Come by and talk to me about them.

Lab Personnel:
Donna Woulfe, PhD - Research Associate
Li Zhu, PhD - Research Associate
Nicolas Prevost - Graduate Student
Alicia Morgans - Medical Student
Vivian Lee - Medical Student
Honghua Yang - Technician
Hong Jiang - Technician
Jie Wu - Technician