BCM Department of Medicine

Training Opportunities in Thrombosis Research

It is our goal to attract both MD and PhD trainees into careers of academic thrombosis research. There are opportunities for training in both clinical and basic research in the area of thrombosis and hemostasis. Most of our faculty are members of Graduate Training Programs, various Core Facilities and Centers. For example, Drs. Bray and López are members of the Cardiovascular Sciences Graduate Training Program and Dr. López is also a member of the Department of Genetics Graduate Training Program. Dr. Cruz is a member of the Keck Center for Computational and Structural Biology.

Thrombosis Research Program Faculty

Name/Degree	Research Interest
Bray, Paul F., MD	Integrin aIIbb3, thrombosis risk factors, hormonal effects on platelets

Dong, Jing-fei, MD, PhD	Rheology & ADAMTS13
Hoots, Keith, MD	Hemophilia, DIC
Kleiman, Neal S., MD	Coronary thrombosis
Kroll, Michael H., MD	Platelet signaling
López, Jose A., MD	Platelet adhesion, GP1b-IX-V
Moake, Joel L., MD	Thrombotic thrombocytopenic purpura
Rice, Lawrence, MD	Heparin-induced thrombocytopenia
Smith, C. Wayne, MD	Integrin biology, platelet-leukocyte interactions
Thiagarajan, P., MD	Antiphosopholipid syndrome, lupus anticoagulant
Afsharkhargan, Vahid, MD	Role of complement in thrombosis
Cruz, Miguel, PhD	Von Willebrand Factor, collagen receptors
Teruya, Jun, MD, DSc	Thrombophilia, diagnostics

There are several areas of training in which our program is especially strong, and which will be briefly mentioned.

1. Rheology. Mechanisms to achieve hemostasis in the arterial tree have had to evolve to contend not only with faster blood flow but also with the increased shear stress that accompanies increased blood velocity. Shear stress—the frictional force between two adjacent infinitesimally thin laminae of a viscous fluid—increases exponentially from the center to the periphery of a cylindrical blood vessel. Hence, in the setting of injury to the arterial wall, shear stress not only acts to limit the ability of platelets to adhere to the site of injury but also as a peeling force to remove the adherent platelets. Blood platelets have evolved several interesting mechanisms for dealing with the conditions of arterial flow. First, they are the smallest and least dense formed elements of the blood and hence are pushed to the periphery of the blood stream by the larger erythrocytes and leukocytes, where they are able to continuously sample the wall for defects. Second, both of the molecules involved in the initial step of platelet adhesion, the GP Ib-IX-V complex and vWf, have structural features particularly well suited for function under shear stress. Glycoprotein Iba, the ligand-binding subunit of the GP Ib-IX-V complex, has a long mucin-like stalk that holds the ligand-binding domain high above the plasma membrane where it is available to bind its ligands and is more susceptible to the influence of shear stress. vWf assumes a globular structure that may become unfurled by shear stress, exposing previously cryptic binding sites. Finally, the observation that the extent of platelet adhesion increases with increased shear stress suggests that the GP Iba-vWf bond may function as a “catch-bond” capable of resisting shear stress and tension.
Shear stress may also facilitate the generation of transmembrane signals by exerting traction on receptors bound to extracellular ligands (e.g. the activation under shear of platelets attached to immobilized vWf, which activates the integrin aIIbb3 and allows the platelets to adhere firmly). Evidence now also exists that shear stress enhances the membrane disruption that precedes the development of platelet procoagulant activity and microvesiculation. Thus, virtually every aspect of arterial thrombosis is influenced by blood flow and the forces it generates.

In the past several years, engineering principles have been used to design model systems that simulate flow in injured, narrowed, or branched arteries. These systems, which include the cone-and-plate viscometer and the parallel-plate flow chamber, allow the application of precise shear forces to both cell suspensions and to adherent cells. In addition, they allow the development of in vitro models to evaluate the role of shear stress in platelet adhesion and thrombus formation. Any evaluation of the molecular interactions associated with arterial thrombosis must take into account the effect of flow and shear stress to ascertain their relevance to the in vivo situation.
Many of the projects of our trainees will include investigations into the role of shear stress. One of the world's leaders in this area of investigation is Larry McIntire, PhD of Rice University. Dr. McIntire has trained many of our faculty in the use of various systems, that allow studies of the rheologic effects on blood and thrombus formation. In addition, the intravital microscopy set-up of Dr. Smith also permits evaluation of shear effects on thrombus formation in the intact vessel of a living animal.

2. Animal Models. 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. 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.

3. Clinical Research Training/Genetic Epidemiology.
We have assembled an exceptionally strong faculty for training involving human subjects. Many of the Thrombosis Research Program Faculty, including Drs. Bray, Afsharkharghan, Dong, López, Moake, Teruya and Thiagarajan, have active clinical research interests. The Clinical Research Program Faculty has a broad base of expertise and includes: hands-on clinical (Drs. Hoots, Kleiman and Rice), clinical coagulation laboratory (Drs. Teruya and Thiagarajan), clinical epidemiology/design/analysis (co-mentors Drs. Carol Ashton and Rebecca Beyth), genetic epidemiologist (co-mentors Drs. Boerwinkle and Leal). The ability to perform translational thrombosis research and provide training for our predoctoral and postdoctoral fellows is greatly facilitated by the fact that mentors on this Training Grant are the Directors of the Thrombosis Core Laboratory, the Coagulation laboratories at The Methodist Hospital, Texas Children's Hospital, and the Michael E. DeBakey VA Medical Center, the Kleberg Genotyping Center, the Baylor DNA Sequencing Core, the Center for Quality Care and Utilization Studies, the Baylor Human Genome Sequencing Center, the Center for Cell and Gene Therapy, Texas Children’s Cancer Center and Hematology Service, and the Baylor Sickle Cell Center.

Trainees will also have the opportunity to participate in Baylor's Clinical Scientist Training Program (CSTP), a multidisciplinary didactic program committed to facilitate and promote the education and training of highly motivated students to become successful, independent clinical investigators and future leaders in academic medicine and biomedical research. Both a Ph.D. and a Master's degree in Clinical Investigation are now available at Baylor. The CSTP curriculum involves formal didactic instruction in the essential elements of clinical investigation. The core curriculum exposes trainees to concepts and methods employed in the broad spectrum of clinical research disciplines, including the fundamentals of clinical investigation, and introductions to biometry and epidemiology. Topics covered in the course include the importance of hypothesis-based research, research design, clinical epidemiology, decision analysis, ethical issues in biomedical research, statistics, scientific funding and writing research proposals, critical appraisal of the biomedical literature, and scientific writing.

Email: medicine@bcm.tmc.edu
URL: http://public.bcm.tmc.edu/medicine/trclin.html (Modified:August 18, 2004)