Heads of Laboratories
Physician in Chief, David Rockefeller Professor
Vice President for Medical Affairs
Allen and Frances Adler Laboratory of Blood and Vascular Biology
When blood vessels break, platelets stop the bleeding by adhering to the damaged vessel walls. Coller’s research focuses on molecular interactions between blood cells and blood vessels, and on 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, Coller established the platelet αIIbβ3 (GPIIb/IIIa) receptor as an important target for antithrombotic therapy. This led him to develop monoclonal antibodies to the platelet αIIbβ3 receptor that inhibit platelet aggregation. Working with scientists at Centocor, 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 five million patients worldwide have been treated with abciximab.
Current research in Coller’s lab focuses on multiple areas of platelet physiology. Among them is the genetic disorder Glanzmann thrombasthenia, which produces hemorrhage as a result of an abnormality of the platelet αIIbβ3 receptor. Coller and his lab members are studying the precise genetic and protein abnormalities responsible for the disease, as well as variants in the genes for the receptor (ITGA2B and ITGB3) identified in the general population by next-generation sequencing.
Other areas of blood and platelet physiology that the lab is studying include:
Integrin structure and activation. Integrins, including platelet αIIbβ3 and αVβ3, 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 ligands. Most recently, nanodisc technology coupled with electron microscopy and three-dimensional reconstruction have been employed to address these questions.
High-throughput screening and structure-guided design. The Coller lab identified a compound, RUC-1, that inhibits ligand binding to platelet αIIbβ3. Structure-guided modifications of it led to the development of another compound, RUC-4, that is approximately 100 times more potent and has a novel mechanism of action as a pure antagonist. RUC-4 is currently being developed for prehospital therapy for myocardial infarction.
Platelet TGF-β1.The Coller lab discovered that platelet TGF-β1can be activated by shear forces, and studies are under way to assess the biological significance of this finding in several model systems.
Integrin αVβ3. With support from the Tri-Institutional Therapeutic Discovery Institute, the Coller lab is studying the impact of pure antagonists of αVβ3 on a variety of pathological processes, including sickle cell disease, osteoporosis, and herpes virus infection.
New York University School of Medicine
Internship in medicine, 1970–1971
Residency in medicine, 1971–1972
Clinical Associate, 1972–1974
Staff Physician, 1974–1976
National Institutes of Health
Assistant Professor, 1976–1978
Associate Professor, 1978–1982
Associate Director for Biomedical Research, 1992–1993
Distinguished Service Professor, 1993
State University of New York at Stony Brook
Mount Sinai School of Medicine
Vice President for Medical Affairs, 2001–
Director, Center for Clinical and Translational Research on Diseases of the Digestive System, 2012–
The Rockefeller University
Physician in Chief, 2001–
Director, Center for Clinical and Translational Science, 2001–
The Rockefeller University Hospital
National Research Achievement Award, American Heart Association, 1998
Warren Alpert Foundation Award, 2001
Pasarow Award, 2005
Karl Landsteiner Memorial Award, 2013
Gill Award, University of Kentucky Gill Heart Institute, 2016
National Academy of Sciences
National Academy of Medicine
American Academy of Arts and Sciences
Zafar, H. et al. αIIbβ3 binding to a fibrinogen fragment lacking the γ-chain dodecapeptide is activation dependent and EDTA inducible. Blood Adv 1, 417–428 (2017).
Buitrago, L. et al. αIIbβ3 variants defined by next generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia. Proc. Natl. Acad. Sci. U.S.A. 112, E1898–E1907 (2015).
Li, J. et al. RUC-4: a novel αIIbβ3 antagonist for prehospital therapy of myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 34, 2321–2329 (2014).
Choi, W.S. et al. Three-dimensional reconstruction of intact human integrin αIIbβ3: new implications for activation-dependent ligand binding. Blood 122, 4165–4171 (2013).
Zhu, J. et al. Structure-guided design of a high-affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg2+ binding to the MIDAS. Sci. Transl. Med. 4, 125ra32 (2012).