Heads of Laboratories
Senior Attending Physician
Frederick Henry Leonhardt Professor
Laboratory of Biochemical Genetics and Metabolism
breslow@rockefeller.edu
Atherosclerotic disease, the hardening of the arteries that underlies coronary heart disease, stroke and peripheral vascular disease, is responsible for about 40 percent of the deaths in the United States each year. It is a complex genetic disease involving multiple genes and important gene-environment interactions. Dr. Breslow’s laboratory explores the genetic basis of atherosclerosis, working to determine what makes certain individuals more or less susceptible to this disease, and pioneers novel therapies to fight it.
Dr. Breslow’s laboratory takes advantage of the availability of human populations, mouse models, genomic databases, high-density SNP chips and gene expression microarrays to detect genetic variations underlying atherosclerosis susceptibility in order to understand the complex genetic basis of this disease. Susceptibility to atherosclerosis is associated with abnormal levels of two types of cholesterol-carrying lipoproteins — low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). Dr. Breslow has studied the apolipoproteins that coat lipoprotein particles, which affect the synthesis, processing and breakdown of these lipoproteins and in some cases are closely related to coronary heart disease. Dr. Breslow’s lab created the first mouse model of atherosclerosis by removing the gene for apolipoprotein E (apo E), a protein found on the surface of several lipoproteins. By breeding the apo E knockout trait to different inbred genetic backgrounds, they observed varying amounts of atherosclerosis, providing evidence for modifier genes. Using mouse genetics, the Breslow lab is identifying new genes and pathways involved in atherosclerosis susceptibility. Human equivalents of the mouse genes are also being studied to see if they explain why some people get heart attacks at an early age and others seem almost immune.
In a second project, Dr. Breslow’s lab has used gene expression microarrays to identify mouse liver genes whose expression is regulated by dietary cholesterol. This work led to the discovery of a new subclass of genes that code for proteins containing domains capable of transporting cholesterol within cells. Another cholesterol-regulated gene discovered by this approach codes for an enzyme capable of destroying the LDL receptor, which clears LDL from the bloodstream. Inhibition of this enzyme could result in more LDL receptors reaching the cell surface, ultimately lowering LDL cholesterol levels.
Finally, in a collaborative project with Rockefeller’s Jeffrey M. Friedman and Markus Stoffel, Dr. Breslow is studying an isolated population on the Micronesian island of Kosrae. Through family data, clinical and laboratory tests and determination of 600,000 genetic markers in each adult Kosraen, the investigators are identifying genes that predispose an individual to obesity, diabetes, abnormal lipid levels and high blood pressure. The results may be useful in diagnosing susceptibility and may lead to new therapies. During the past two decades, Dr. Breslow’s lab has cloned and characterized most of the apolipoprotein genes. They have discovered that human genetic variation in apo E resulted from three different apo E types. Specific patterns of inheritance of apo E are linked to LDL cholesterol levels, atherosclerosis, Alzheimer’s disease susceptibility and even longevity. Dr. Breslow was the first to identify at the molecular level a human mutation causing atherosclerosis susceptibility, an apo A-I mutation that causes HDL deficiency and premature coronary heart disease. His research has shown that overproduction of apo CIII is a major determinant of high triglyceride levels, and that triglyceride-lowering drugs called fibrates act mainly by decreasing apo CIII production.
CAREER
Dr. Breslow earned his A.B. and M.A. in 1963 and 1964, respectively, both in chemistry, from Columbia University. He received his M.D. from Harvard Medical School in 1968. After an internship and residency in pediatrics at Boston Children’s Hospital and a post as staff associate at the Molecular Disease Branch of the National Heart and Lung Institute, he returned to Boston Children’s Hospital in 1973 as chief of the metabolism division and assistant and then associate professor of pediatrics at Harvard Medical School. He joined Rockefeller as professor in 1984 and was named Frederick Henry Leonhardt Professor in 1986. He is a senior attending physician at The Rockefeller University Hospital, where he also served as physician in chief in the early 1990s.
Dr. Breslow received the 2005 New York City Mayor’s Award for Excellence in Science and Technology. He is a past president of
the American Heart Association and received its Gold Heart Award in 2001. He was awarded the Bristol-Myers Squibb Award for
Distinguished Achievement in Cardiovascular Research in 2000, and was elected to the National Academy of Sciences in 1995 and
the Institute of Medicine in 1997.
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