Heads of Laboratories
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, and genomic sequencing 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 cholesterol-carrying lipoproteins — low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). Dr. Breslow has studied the apolipoproteins that coat lipoproteins, which affect the synthesis, processing and breakdown of lipoproteins and in some cases are related to coronary heart disease. He has cloned genes for apolipoproteins and made induced mutant mouse models to study these genes’ functions in vivo.
Dr. Breslow’s laboratory created the first mouse model of atherosclerosis by knocking out the gene for apolipoprotein E (apo E), found on the surface of several lipoproteins. His laboratory bred the apo E knockout trait to different inbred genetic backgrounds, resulting in varying amounts of atherosclerosis and providing evidence for modifier genes. The Breslow laboratory has undertaken mouse crosses and quantitative trait locus mapping to identify new genes and pathways involved in atherosclerosis susceptibility.
In another project, Dr. Breslow’s lab has used gene expression microarrays to identify mouse liver genes whose expression is regulated by dietary cholesterol, work that has led to a new subclass of genes linked to cholesterol transport 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 allow more receptors to reach the cell surface, lowering LDL cholesterol levels.
Finally, in a collaborative project with Rockefeller’s Jeffrey M. Friedman and investigators at Columbia, Harvard, MIT and Yale, Dr. Breslow is studying an isolated population on the Micronesian island Kosrae. Through family data, clinical and laboratory tests and determination of 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.
Past accomplishments include discovering that human genetic variation in apo E resulted from three different apo E types. Specific patterns of inheritance of these apo E types are linked to LDL cholesterol levels, atherosclerosis, Alzheimer’s disease 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.
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 is a past president of the American Heart Association and received its Gold Heart Award for exceptional service in 2001. For his research contributions, Dr. Breslow received the American Heart Association’s Basic Research Prize in 1994, the Bristol-Myers Squibb Award for Distinguished Achievement in Cardiovascular Research in 2000, the New York City Mayor’s Award for Excellence in Science and Technology in 2005 and the American Heart Association’s Lifetime Research Achievement Award in 2010. Dr. Breslow was elected to the National Academy of Sciences in 1995 and the Institute of Medicine in 1997.
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