Many of the crucial genes involved in hemostasis and thrombosis, including platelet adhesive glycoproteins, signaling receptors, coagulation factors and fibrinolytic factors have been studied in animal models, either by knock-outs, knock-ins or transgenic animals. Substantial insights have been made through the study of these animals, however there is a tremendous amount of work yet to be done with existing animals and opportunity to generate new strains to better understand the complexities of in vivo thrombosis.
Of course, not all of these mentors' studies have pertained directly to thrombosis, but several that have will be mentioned here. Dr. Bray is using eNOS-/- mice to study the role of this enzyme on platelet reactivity. He is also using ER a, ER b and PR deficient mice to characterize gender differences in platelet fibrinogen binding and thrombosis. Dr. Bray has also screened 5 different mouse strains for varying levels of platelet membrane glycoproteins, and identified strain differences that will be used in genetic approaches for characterizing gene expression. Dr. López has made a dominant negative Syk mouse that will be used to dissect this role of this key signaling molecule in platelet activation, adhesion and aggregation. His lab has also recently generated mice that allow targeted expression in megakaryocytes using the cre-lox system.
Both Drs. Bray and López have developed extensive expertise in manipulating mouse platelets, assessing their adhesive and signaling properties. Dr. Arthur L. Beaudet (Chair, Genetics Department) generated LDL receptor deficient mice as a model for state-of-the-art helper-dependent adenoviral vector gene therapy of hypercholesterolemia. He is collaborating with Dr. López to uncover the basis for the thrombocytopenia that occurs with this gene therapy approach. Dr. Smith has generated a number of mice deficient in cell adhesion molecules (Mac-1, LFA-1, ICAM-1, and CD18) to leukocyte function and migration.
Thus, trainees will be ample opportunity (and be encouraged) to become skilled with mouse genetics and manipulating mouse genes as a valuable tool for studying normal and abnormal thrombosis and hemostasis.