Heads of Laboratories
When blood vessels break, platelets stop the bleeding by adhering to the damaged vessel walls. They then aggregate with each other and facilitate thrombin production and fibrin deposition, both of which are key components of blood coagulation. Dr. Coller’s research focuses on molecular interactions between blood cells and blood vessels as they relate to platelet physiology, thrombosis, vascular biology and adhesion phenomena, with the ultimate goal of developing new therapies for thrombotic diseases such as heart attack and stroke.
Because platelets play a vital role in blood coagulation, deficiencies in their numbers or function can result in excessive bleeding. But when platelets adhere to and aggregate on blood vessels narrowed by atherosclerosis, they can close off the blood vessel and cause a myocardial infarction (heart attack) or stroke.
By studying the receptors responsible for platelet aggregation and patients who genetically lack the receptors, Dr. Coller established the platelet αIIbβ3 (GPIIb/IIIa) receptor as an important target for antithrombotic therapy. This led him to develop monoclonal antibodies to the αIIbβ3 receptor that inhibit platelet aggregation. Working with scientists at Centocor, Dr. Coller helped develop a derivative of one of these antibodies into the drug abciximab, which was approved in 1994 to prevent ischemic complications of percutaneous coronary interventions, such as stent placement in patients with myocardial infarction and related conditions. More than four million patients worldwide have been treated with abciximab.
Current research in Dr. Coller’s lab focuses on multiple areas of platelet physiology. One of those areas is the genetic disorder Glanzmann thrombasthenia, which produces hemorrhage as a result of an abnormality of the αIIbβ3 receptor. Dr. Coller and his lab members are studying the precise genetic and protein abnormalities responsible for the disease.
Other areas of blood and platelet physiology that the lab is studying include:
1) Integrin structure and activation: Integrins (including αIIbβ3) are transmembrane glycoprotein receptors. Through site-directed mutagenesis, molecular dynamics, electron microscopy and x-ray crystallography studies, the lab is studying the mechanisms by which the receptors undergo a transition from an inactive to an active conformation with high affinity for ligand. Most recently, nanodisc technology has been developed to address these questions.
2) High throughput screening and structure-guided design: The Coller lab identified a single compound out of more than 33,000 tested that inhibits ligand binding to αIIbβ3. Structure-guided modifications of this led to a compound (RUC-2) that is approximately 100 times more potent, and this compound is being evaluated for its therapeutic potential. Compounds from an additional high throughput screen are under investigation.
3) Platelet TGF-β1: The Coller lab discovered that platelet TGF-β1, a potent modifier of gene transcription and cellular behavior, can be activated by shear forces, and studies are under way to assess the biologic significance of this finding in model systems and human diseases, including aortic stenosis and sickle cell disease.
4) Murine models of myocardial infarction: To better study myocardial infarction in mice, the Coller lab is using ultrasound-guided techniques to induce myocardial infarctions that better simulate the pathophysiology of the human disease than current surgical methods.
Dr. Coller received his B.A. from Columbia University in 1966 and his M.D. from the New York University School of Medicine in 1970. He completed his residency in internal medicine at Bellevue Hospital in New York City and received advanced training in hematology and clinical pathology at the National Institutes of Health. He was at Stony Brook University from 1976 to 1993, and from 1993 to 2001 he served as a professor of medicine and chairman of the department of medicine at Mount Sinai School of Medicine. Dr. Coller came to Rockefeller in 2001 as the first David Rockefeller Professor, head of the Laboratory of Blood and Vascular Biology, physician in chief of The Rockefeller University Hospital and vice president for medical affairs. Dr. Coller also serves as principal investigator of the university’s Clinical and Translational Science Award, director of The Rockefeller University Center for Clinical and Translational Science, and director of the Center for Basic and Translational Research on Disorders of the Digestive System.
Dr. Coller received the Robert J. and Claire Pasarow Foundation Award in 2005, the Warren Alpert Foundation Award in 2001 and a National Research Achievement Award from the American Heart Association in 1998. He is a member of the Institute of Medicine, the National Academy of Sciences and the American Academy of Arts and Sciences. Dr. Coller is a past president of the American Society of Hematology and served as the founding president of the Society for Clinical and Translational Science.
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