Dr. Breslow’s laboratory takes advantage of the availability of genomic databases, mouse models, gene expression microarrays and high-density methods to detect genetic variation to study atherosclerosis in both mice and humans in order to understand the complex genetic basis of atherosclerosis susceptibility and identify important gene-diet interactions.

Susceptibility to atherosclerosis is associated with abnormal levels of two types of cholesterol-carrying lipoproteins — low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). Genes that affect the synthesis, processing and breakdown of these lipoproteins are closely linked to 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 vary from person to person, which may explain why some people get heart attacks at an early age and others seem 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 blood stream. 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 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 hope to identify which genes predispose an individual to obesity, diabetes, abnormal lipid levels and high blood pressure. The results may be useful in diagnosing which individuals are susceptible, and may lead to new mechanism-based therapies.

During the past two decades, Dr. Breslow’s lab has cloned and characterized most of the apolipoprotein genes. They 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 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, National Institutes of Health, Bethesda, he returned to Boston Children’s Hospital in 1973 as chief of the metabolism division and associate professor of pediatrics at Harvard Medical School. He joined Rockefeller University as professor in 1984 and was named Frederick Henry Leonhardt Professor in 1986. He is a senior 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. He was elected to the Institute of Medicine of the National Academy of Sciences in 1997 and to the National Academy of Sciences in 1995.