Heads of Laboratories
Senior Attending Physician
Frederick Henry Leonhardt Professor
Laboratory of Biochemical Genetics and Metabolism
Atherosclerotic disease, the hardening of the arteries that underlies coronary heart disease, stroke, and peripheral vascular disease, is a complex genetic condition responsible for about 40 percent of the deaths in the United States each year. Breslow’s laboratory explores the genetic and environmental bases of atherosclerosis to determine what makes certain individuals more or less susceptible to this disease, and also pioneers novel therapies.
Susceptibility to atherosclerosis is associated with abnormal levels of plasma lipoproteins. Breslow’s studies have focused on molecules called apolipoproteins, which coat lipoprotein particles and determine their synthesis, processing, and breakdown.
His laboratory cloned the genes for most of the apolipoproteins and made induced mutant mouse models, including the first mouse model of atherosclerosis, to study how these genes function in vivo. The atherosclerosis model was made by knocking out the gene for apolipoprotein E (apo E), which is found on the surface of several lipoproteins. By breeding the apo E knockout trait to different inbred genetic backgrounds, Breslow and his colleagues produced varying amounts of atherosclerosis and evidence for modifier genes. Using these methods, the lab is identifying new genes and pathways involved in atherosclerosis susceptibility.
By using gene expression microarrays to identify mouse liver genes whose expression is regulated by dietary cholesterol, the Breslow lab has uncovered a new subclass of START-domain containing genes linked to cholesterol transport within cells. Using the same approach, they also discovered another cholesterol-regulated gene coding for a protein called PCSK9. His lab showed that PCSK9 was capable of destroying the LDL receptor, which clears LDL from the bloodstream. These findings helped the development of two monoclonal antibody inhibitors of PCSK9, approved by the FDA in 2015 for further lowering LDL cholesterol levels in patients receiving statins, as well as in patients with statin intolerance.
Other 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. Breslow was the first to identify, at the molecular level, a human mutation causing atherosclerosis susceptibility, an apo A-I mutation that caused HDL deficiency and premature coronary heart disease. His research has also 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.
Recently, the Breslow lab discovered a serum peptide, generated at sites of inflammation by factor XIIa, that dramatically promotes CCR7-induced leukocyte migration. A medicinal chemistry effort has generated sensitive and specific small molecular weight inhibitors of factor XIIa that prevent the generation of this peptide, and preliminary in vivo studies have shown efficacy in mouse models of inflammatory disease.
In a collaborative project with Jeffrey M. Friedman and investigators at Columbia, Harvard, MIT, and Yale, Breslow has studied an isolated population on the Micronesian island of Kosrae. Through family data, clinical and laboratory tests, and determination of genetic markers in each adult Kosraen, the investigators have identified genes that predispose an individual to obesity, diabetes, abnormal lipid levels, and high blood pressure.
A.B. in chemistry, 1963
M.A. in chemistry, 1964
Harvard Medical School
Internship in pediatrics, 1968–1969
Residency in pediatrics, 1969–1970
Boston Children’s Hospital
National Heart, Lung, and Blood Institute, 1970–1973
Assistant Professor, 1974–1980
Associate Professor, 1980–1983
Harvard Medical School
Senior Associate, 1981–1983
Boston Children’s Hospital
Frederick Henry Leonhardt Professor, 1984–
Director, Sackler Center for Biomedicine and Nutrition Research, 2014–
The Rockefeller University
Senior Physician, 1984–
Physician in Chief, 1991–1992
The Rockefeller University Hospital
E. Mead Johnson Award, Society for Pediatric Research, 1984
National Institutes of Health MERIT Award, 1986
Heinrich Wieland Prize, Boehringer Ingelheim Foundation, 1991
Pasarow Award, 1994
Basic Research Prize, American Heart Association, 1994
Bristol-Myers Squibb Award, 2000
Gold Heart Award, American Heart Association, 2001
New York City Mayor’s Award for Excellence in Science and Technology, 2005
Lifetime Research Achievement Award, American Heart Association, 2010
National Academy of Sciences
National Academy of Medicine
German National Academy of Sciences Leopoldina
Ponda, M.P. et al. A randomized clinical trial in vitamin D-deficient adults comparing replenishment with oral vitamin D3 with narrow-band UV type B light: effects on cholesterol and the transcription profiles of skin and blood. Am. J. Clin. Nutr. 105, 1230–1238 (2017).
Ponda, M.P. and Breslow, J.L. Serum stimulation of CCR7 chemotaxis due to coagulation factor XIIa-dependent production of high-molecular-weight kininogen domain 5. Proc. Natl. Acad. Sci. U.S.A. 113, E7059–E7068 (2016).
Rodriguez, J.M. et al. Altered expression of Raet1e, a major histocompatibility complex class 1-like molecule, underlies the atherosclerosis modifier locus Ath11 10b. Circ. Res. 113, 1054–1064 (2013).
Garbarino, J. et al. STARD4 knockdown in HepG2 cells disrupts cholesterol trafficking associated with the plasma membrane, ER, and ERC. J. Lipid Res. 53, 2716–2725 (2012).
Burkhardt, R. et al. Trib1, a novel lipid and myocardial infarction associated gene, regulates hepatic lipogenesis and VLDL production in mice. J. Clin. Invest. 120, 4410–4414 (2010).