Gender	Female
E-mail	debbie.french@mssm.edu

Integrins are integral membrane protein heterodimeric complexes that mediate cell-cell and cell-extracellular matrix (ECM) adhesive interactions. The platelet integrin glycoprotein (GP) IIb/IIIa receptor plays a critical role in both hemostasis and thrombosis. The involvement of GPIIb/IIIa in platelet aggregation is underscored by the fact that aggregation is absent in patients with the bleeding disorder Glanzmann thrombasthenia. This disease is characterized by a functional absence of GPIIb/IIIa receptors on the platelet surface. The clinical significance of the platelet GPIIb/IIIa receptor is highlighted by the fact that platelet aggregation plays an important role in pathologic thrombi formation. The biologic link between GPIIb/IIIa and platelet aggregation is based on the highly regulated binding activity of this receptor. Signal transduction mechanisms mediating platelet aggregation trigger a conformational change in the receptor to a high affinity state that is competent to bind soluble ligand. The binding sites on ligands for integrin receptors have been identified from structural studies as short peptide sequences that are often presented on extended loops. Less precise information is available concerning the sites within integrins that recognize ligands and this information is fundamental to understanding the molecular events that lead to ligand-binding activity, specificity, and secondary events triggered by ligand-binding. The emerging picture of platelet GPIIb/IIIa receptor binding is that the ligand-binding pocket is comprised of crucial residues brought together in the three-dimensional structure of the receptor complex. Interestingly, Glanzmann thrombasthenia provides a paradigm for the successful inhibition of GPIIb/IIIa receptors in cardiovascular disease by pharmacologic agents. We are studying the structure/function and biogenesis of this receptor by characterizing naturally occurring inherited mutations in the genes encoding GPIIb and GPIIIa in patients with Glanzmann thrombasthenia.

Projects in the laboratory include: 1) The identification of pathways and protein mediators that target the degradation of normal and mutant integrin receptor subunits and 2) The identification of structural and signal transductions mechanisms underlying ligand-binding function of integrin receptors.

Autoantibodies to cell membrane phospholipids are associated with the anti-phospholipid syndrome which results in venous and arterial thrombosis and recurrent pregnancy loss. The mechanism of this syndrome has remained elusive. The long term goals of this project are to determine how anti-phospholipid antibodies induce thrombosis and cause disease. A collaborator, Dr. Jake Rand, has recently described a novel mechanism for the pathogenesis of disease and hypothesized that anti-phospholipid antibodies disrupt an anticoagulant layer of annexin-V on negatively-charged cell membranes resulting in the generation of procoagulant surfaces and thrombosis. We propose that anti-phospholipid antibodies from patients with this syndrome disrupt the protective cluster of annexin-V on these cell surfaces, thus increasing the availability of phospholipids for coagulation reactions that lead to thrombosis. We will test this hypothesis by analysis of anti-phospholipid antibodies for displacement of annexin-V on phospholipid surfaces, for acceleration of plasma coagulation reactions, and ultimately for the generation of thrombosis in animal models.

Projects in the laboratory include: 1) Functional characterization of human anti-phospholipid antibodies from an Fab-expressing phage display library generated from patients with the anti-phospholipid syndrome and 2) Identification of the fine specificity and amino acid sequence motif recognized by anti-phospholipid antibodies using a peptide library.

Grimaldi CM, Chen F, Scudder LE, Coller B, French D. A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta 3) in a Chinese patient with Glanzmann's thrombasthenia. Blood 1996 Sep 1; 88(5): 1666-75.

French D, Coller B. Hematologically important mutations: Glanzmann thrombasthenia.. Blood Cells Mol Dis 1997 23(1):39-51.

Grimaldi CM, Chen F, Wu C, Weiss HJ, Coller B, French D. Glycoprotein IIb Leu214Pro mutation produces glanzmann thrombasthenia with both quantitative and qualitative abnormalities in GPIIb/IIIa. Blood 1998 Mar 1; 91(5): 1562-71.

French D, Coller B, Usher S, Berkowitz R, Eng C, Seligsohn U, Peretz H. Prenatal diagnosis of Glanzmann thrombasthenia using the polymorphic markers BRCA1 and THRA1 on chromosome 17. Br J Haematol 1998 Jul; 102(2): 582-7.

French D, Seligsohn U. Platelet glycoprotein IIb/IIIa receptors and Glanzmann's thrombasthenia. Arterioscler Thromb Vasc Biol 2000 Mar 20(3):607-10.

Haque N, Zhang X, French D, Li J, Poon M, Fallon J, Gabel BR, Taubman M, Harpel P. CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells. Circulation 2000 Aug 15; 102(7): 786-92.