Jan Breslow

Last updated
Jan Breslow
Alma mater
Awards Heinrich Wieland Prize (1991)
Scientific career
Institutions

Jan Leslie Breslow (born 1943) [1] [2] is an American physician and medical researcher who studies atherosclerosis. As of 2017, he is Frederick Henry Leonhardt Professor at Rockefeller University and directs the university's Laboratory of Biochemical Genetics and Metabolism.

Contents

Biography

Breslow attended Columbia College, Columbia University, gaining AB (1963) and MA (1964) degrees in chemistry. He then studied at Harvard Medical School, receiving his MD in 1968. He worked in pediatric medicine at the Boston Children's Hospital (1968–70) and then held a post-doctoral position at the National Heart, Lung, and Blood Institute (1970–73). [1] [3]

Human apolipoprotein E PBB Protein APOE.jpg
Human apolipoprotein E

In 1973, he took up a post as head of the metabolism division of Boston Children's Hospital, as well as successively instructor, assistant and associate professor in pediatric medicine at Harvard Medical School. In 1984, he moved to Rockefeller University as a professor, and in 1986, was appointed Frederick Henry Leonhardt Professor at the Laboratory of Biochemical Genetics and Metabolism. [1] [3] In 2014, he was appointed director of the university's Sackler Center for Biomedicine and Nutrition. [3] He also works at Rockefeller University Hospital as a senior physician and was physician-in-chief in the 1990s. [1] [3]

Research

Breslow's research has focused on the genetic factors that govern an individual's predisposition to develop atherosclerosis. [4] He started to work on the genetics of cholesterol handling in the late 1970s, [5] and in the early 1980s, with Vassilis Zannis, he was one of the earliest to dissect the different variants of human apolipoprotein E (ApoE), a component of very low-density lipoprotein. [6] People with different ApoE variants are now known to have different risks not only of heart disease but also of Alzheimer's disease. [4] In 1992, his group found that deleting the mouse gene for ApoE caused the animals to develop elevated blood cholesterol levels and atherosclerosis within around 6 months, on a normal diet. [7] Nobuyo Maeda's group at the University of North Carolina at Chapel Hill also independently created ApoE knockouts (apoe−/−) that developed atherosclerosis at the same time. [8] [9] [10] The ApoE knockout was the earliest mouse model of the disease, and has been widely used in atherosclerosis research. [10] [11] [12]

Human PCSK9 Protein PCSK9 PDB 2p4e.png
Human PCSK9

His group has subsequently researched other genes associated with atherosclerosis, and for example, in 2003, were among the first to identify and characterize PCSK9 , which encodes an enzyme acting in a novel cholesterol regulatory pathway. [13] Antibodies targeting PCSK9 were approved by the US FDA as a novel class of cholesterol-lowering drugs in 2015. [14]

Awards and honours

Breslow is an elected fellow of the American Society for Clinical Investigation (1984), [2] US National Academy of Sciences (1995), Deutsche Akademie der Naturforscher Leopoldina (1996) [15] and the Institute of Medicine (1997). [4] He served as president of the American Heart Association – using the position to lobby vigorously for more government funding for research into heart disease [16] – and has received several awards from the association, including their Lifetime Research Achievement Award in 2010. [1] He has also served as vice president of the American Society for Clinical Investigation. [4] He has won the E. Mead Johnson Award of the American Academy of Pediatrics (1984), the Heinrich Wieland Prize (1991) and the Bristol-Myers Squibb Award for Cardiovascular Research (2000). [1] [4] In March 2013, Rockefeller University organized a symposium entitled "Genetics of Lipid Disorders and Atherosclerosis" to mark his seventieth birthday. [17]

Personal life

Breslow is married to Marilyn G. Breslow, an investment manager and sculptor; the couple have two sons. [18] [19] Breslow is one of the signatories of a letter entitled "No Need to Panic About Global Warming", which was published in The Wall Street Journal in 2012. [20]

Selected publications

Related Research Articles

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<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Lipoprotein</span> Biochemical assembly whose purpose is to transport hydrophobic lipid molecules

A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

<span class="mw-page-title-main">Joseph L. Goldstein</span> American biochemist

Joseph Leonard Goldstein ForMemRS is an American biochemist. He received the Nobel Prize in Physiology or Medicine in 1985, along with fellow University of Texas Southwestern researcher, Michael Brown, for their studies regarding cholesterol. They discovered that human cells have low-density lipoprotein (LDL) receptors that remove cholesterol from the blood and that when LDL receptors are not present in sufficient numbers, individuals develop hypercholesterolemia and become at risk for cholesterol related diseases, notably coronary heart disease. Their studies led to the development of statin drugs.

<span class="mw-page-title-main">Apolipoprotein</span> Proteins that bind lipids to transport them in body fluids

Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.

Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Apolipoprotein E</span> Cholesterol-transporting protein most notably implicated in Alzheimers disease

Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.

<span class="mw-page-title-main">Apolipoprotein B</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

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<span class="mw-page-title-main">Lipoprotein(a)</span> Low-density lipoprotein containing apolipoprotein(a)

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.

<span class="mw-page-title-main">Apolipoprotein AI</span>

Apolipoprotein AI(Apo-AI) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.

<span class="mw-page-title-main">Apolipoprotein C-III</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.

<span class="mw-page-title-main">Apolipoprotein D</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein D(ApoD) is a protein that in humans is encoded by the APOD gene. Unlike other lipoproteins, which are mainly produced in the liver, apolipoprotein D is mainly produced in the brain and testes. It is a 29 kDa glycoprotein discovered in 1963 as a component of the high-density lipoprotein (HDL) fraction of human plasma. It is the major component of human mammary cyst fluid. The human gene encoding it was cloned in 1986 and the deduced protein sequence revealed that ApoD is a member of the lipocalin family, small hydrophobic molecule transporters. ApoD is 169 amino acids long, including a secretion peptide signal of 20 amino acids. It contains two glycosylation sites (aspargines 45 and 78) and the molecular weight of the mature protein varies from 20 to 32 kDa (see figure 1).

<span class="mw-page-title-main">APOA5</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Apolipoprotein A-II</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein A-II is a protein that in humans is encoded by the APOA2 gene. It is the second most abundant protein of the high density lipoprotein particles. The protein is found in plasma as a monomer, homodimer, or heterodimer with apolipoprotein D. ApoA-II regulates many steps in HDL metabolism, and its role in coronary heart disease is unclear. Remarkably, defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Apabetalone</span> Chemical compound

Apabetalone is an orally available small molecule created by Resverlogix Corp. that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD). In the phase II clinical trial ASSURE in patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels, apabetalone showed no greater increase in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels or incremental regression of atherosclerosis than administration of placebo, while causing a statistically significant greater incidence of elevated liver enzymes. However, pooled analysis of the effect of apabetalone in three phase II clinical trials ASSERT, ASSURE, and SUSTAIN demonstrated increases in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreases in the incidence of major adverse cardiac events (MACE). Reduction of MACE was more profound in patients with diabetes mellitus. In a short-term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone. An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015. The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.

Nobuyo N. Maeda is a Japanese geneticist and medical researcher, who works on complex human diseases including atherosclerosis, diabetes and high blood pressure, and is particularly known for creating the first mouse model for atherosclerosis. Maeda has worked in the United States since 1978; as of 2017, she is the Robert H. Wagner Distinguished Professor at the University of North Carolina at Chapel Hill.

References

  1. 1 2 3 4 5 6 Creating the "Heart-Attack Mouse": A Model for Atherosclerosis, Rockefeller University , retrieved 16 January 2017
  2. 1 2 Jan Leslie Breslow, MD, American Society for Clinical Investigation , retrieved 17 January 2017
  3. 1 2 3 4 Jan L. Breslow, M.D., Rockefeller University , retrieved 16 January 2017
  4. 1 2 3 4 5 Ruth SoRelle (2000), "Jan L. Breslow, MD, Receives 10th Annual Bristol-Myers Squibb Award", Circulation , 101 (23): E9054-5, doi:10.1161/01.CIR.101.23.e9054, PMID   10851226
  5. ↑ Jerry E. Bishop; Michael Waldholz (2014), Genome: The Story of the Most Astonishing Scientific Adventure of Our Time—the Attempt to Map All the Genes in the Human Body, Open Road Media, ISBN   978-1-4976-0753-8
  6. ↑ Robert W. Mahley; Karl H. Weisgraber; Yadong Huang (2009), "Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS", Journal of Lipid Research , 50 (Suppl): S183–88, doi:10.1194/jlr.R800069-JLR200, PMC   2674716 , PMID   19106071
  7. ↑ Andrew S. Plump; Jonathan D. Smith; Tony Hayek; Katriina Aalto-Setälä; Annemarie Walsh; Judy G. Verstuyft; Edward M. Rubin; Jan L. Breslow (1992), "Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells", Cell , 71 (2): 343–53, doi:10.1016/0092-8674(92)90362-g, PMID   1423598, S2CID   29828640
  8. ↑ Sunny H. Zhang; Robert L. Reddick; Jorge A. Piedrahita; Nobuyo Maeda (1992), "Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E", Science , 258 (5081): 468–71, Bibcode:1992Sci...258..468Z, doi:10.1126/science.1411543, PMID   1411543
  9. ↑ The Nobel Prize in Physiology or Medicine 2007: Advanced Information, The Nobel Foundation , retrieved 16 January 2017
  10. 1 2 Jan L. Breslow (1996), "Mouse models of atherosclerosis", Science , 272 (5262): 685–88, Bibcode:1996Sci...272..685B, doi:10.1126/science.272.5262.685, PMID   8614828, S2CID   33508623
  11. ↑ Fatemeh Ramezani Kapourchali; Gangadaran Surendiran; Li Chen; Elisabeth Uitz; Babak Bahadori; Mohammed H. Moghadasian (2014), "Animal models of atherosclerosis", World Journal of Clinical Cases, 2 (5): 126–32, doi: 10.12998/wjcc.v2.i5.126 , PMC   4023305 , PMID   24868511
  12. ↑ Stewart C. Whitman (2004), "A practical approach to using mice in atherosclerosis research", The Clinical Biochemist Reviews, 25 (1): 81–93, PMC   1853358 , PMID   18516202
  13. ↑ Stephen S. Hall (2013), "Genetics: A gene of rare effect", Nature , 496 (7444): 152–55, Bibcode:2013Natur.496..152H, doi: 10.1038/496152a , PMID   23579660
  14. ↑ FDA approves Praluent to treat certain patients with high cholesterol, FDA, 24 July 2015, retrieved 18 January 2017
  15. ↑ "List of Members". www.leopoldina.org. Retrieved 19 October 2017.
  16. ↑ Eliot Marshall (1997), "Lobbyists seek to reslice NIH's pie", Science , 276 (5311): 344–46, doi:10.1126/science.276.5311.344, JSTOR   2893285, PMID   9139352, S2CID   26468264
  17. ↑ A Symposium in Honor of Jan Breslow's 70th Birthday, Rockefeller University, 15 March 2013, retrieved 17 January 2017
  18. ↑ Marilyn G. Breslow, The New York Stem Cell Foundation, retrieved 17 January 2017
  19. ↑ "Marilyn Breslow: Artist Statement", Marilyn Breslow: Sculptor, retrieved 17 January 2017
  20. ↑ No Need to Panic About Global Warming, The Wall Street Journal, 27 January 2012, retrieved 27 February 2020
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