Stanley L. Hazen, MD, PhD
Chairman
The Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
A long term goal of my laboratory is to understand mechanisms through which inflammation contributes to diseases like atherosclerosis and asthma. Several major research programs are currently under investigation. One research program focuses on the role of myeloperoxidase, a leukocyte heme protein, in promoting oxidant stress in vivo, and its participation in cardiovascular diseases. A second area focuses on HDL structure and function. A final area of research interest focuses on the role of intestinal microbiota in cardiometabolic disease.
All research projects rely heavily on chemical and analytical methods to identify specific reactions/products, their mechanisms of formation, and their use as probes to elaborate pathways responsible for disease. Research efforts in each program span from bench-to-bedside, including basic/genetic, cellular, animal model, andhuman clinicalinvestigations.
Lay Summary
A long term goal of my laboratory is to understand the ways in which our immune system contributes to diseases like heart disease and asthma. I have several major areas of focus. One centers on the role of myeloperoxidase, a protein found in white blood cells that plays an important role in fighting infections, but which we have discovered also participates in development of heart diseases. A second area focuses on the role of microbes in our intestines (called gut flora) in heart disease. Another area focuses on the HDL particle (carrier of good cholesterol in the blood).
Experimental data and computational models for downloading
Articles:
1) The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction
Wu, Z.; Wagner, M. A.; Zheng, L.; Parks, J. S.; Shy II, J. M.; Smith, J. D.; Gogonea, V.; Hazen, S. L. Nat. Struct. Mol. Biol. 14, 861-8 (2007).
Computational model:
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1a) All-atom molecular model of the Solar Flares model of nascent HDL (PDB file) liked to nHDL_SF.pdb Also available at mi.caspur.it (accession code PM0074956) |
2) The double super helix model of high density lipoprotein
Wu, Z.; Gogonea, V.; Lee, X.; Wagner, M. A.; Li, X.-M.; Huang, Y.; Arundhati, U.; May, R. P.; Haertlein, M.; Moulin, M.; Gutsche, I.; Zaccai, G.; DiDonato, J.; Hazen, S. L. J. Biol. Chem. 284, 36605-19 (2009).
Experimental data and computational models:
| 2a) Small angle neutron scattering intensities for the protein component of nascent HDL (12 % D2O, collected at the Institute Laue-Langevin, Grenoble, France) linked to nHDL_12_D2O_ILL.dat | |
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2b)The solution low-resolution structure of the protein component of nascent HDL obtained by small angle neutron scattering with contrast variation (12 % D2O, ILL data, PDB file) linked to nHDL_12_D2O_ILL.pdb |
| 2c) Small angle neutron scattering intensities for the lipid component of nascent HDL (42 % D2O, collected at the Institute Laue-Langevin, Grenoble, France) linked to nHDL_42_D2O_ILL.dat | |
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2d)The solution low-resolution structure of the lipid component of nascent HDL obtained by small angle neutron scattering with contrast variation (42 % D2O, ILL data, PDB file) linked to nHDL_42_D2O_ILL.pdb |
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2e) The Double Super Helix model of nascent HDL (PDB file) linked to 3K2S.pdb Also available at www.rcsb.org (accession code 3K2S) |
3) Congruency between biophysical data from multiple platforms and molecular dynamics simulation of the double super helix model of nascent high-density lipoprotein
Gogonea, V.; Wu, Z.; Lee, X.; Pipich, V.; Li, X.-M., Ioffe, I. A.; DiDonato, J.; Hazen, S. L. Biochemistry, 49, 7323-43 (2010).
Experimental and computational models, and data calculated from simulation trajectory:
4) The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering
Wu, Z.; Gogonea, V.; Lee, X.; May, R.P.; Pipich, V.; Wagner, M.A.; Undurti, A.; Tallant, T. C.; Baleanu-Gogonea, C.; Charlton, F.; Ioffe, I. A.; DiDonato, J.A.; Rye, K.-A.; Hazen, S. L. J. Biol. Chem., 286, 12495-508 (2011).
Low resolution structures:
| 4a) Small angle neutron scattering intensities for the protein component of spherical HDL (12 % D2O) linked to sHDL_12_D2O.dat | |
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4b) The solution low-resolution structure of the protein component of spherical HDL obtained by small angle neutron scattering with contrast variation (12 % D2O, PDB file) linked to sHDL_12_D2O.pdb |
| 4c) Small angle neutron scattering intensities for the lipid component of spherical HDL (42 % D2O) linked to sHDL_42_D2O.dat | |
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4d) The solution low-resolution structure of the lipid component of spherical HDL obtained by small angle neutron scattering with contrast variation (42 % D2O, PDB file) linked to sHDL_42_D2O.pdb |
5) The low resolution structure of nascent high density lipoprotein reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion
Gogonea, V.; Gerstenecker, G. S.; Wu, Z.; Lee, X.; Topbas, C.; Wagner, M. A.; Tallant, T. C.; Smith J. D.; Callow, P.; Pipich, V.; Malet, H.; Schoehn, G.; DiDonato, J. A.; Hazen, S. L. J. Lipid Res., in print.
Low resolution structures and computational model:
- Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WHW, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature.(2011) 472(7341):57-63. PMCID: PMC3086762
- Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk. New England Journal of Medicine. (2013) 368(17):1575-84. PMCID: PMC3701945
- Koeth RA, Wang Z, Levison BS, Buffa J, Org E, Sheehy B, Li H, Britt EB, Fu X, Wu Y, Smith JD, DiDonato JA, Chen J, Li H, Wu G, Lewis JD, Warrier M, Brown, JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, and Hazen SL. Intestinal microbiota metabolism of L-Carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. (2013) 19(5): 576-85. PMCID: PMC36501111
- Huang Y, Didonato JA, Levison BS, Schmitt D, Li L, Wu Y, Buffa J, Kim T, Gerstenecker GS, Gu X, Kadiyala CS, Wang Z, Culley MK, Hazen JE, Didonato AJ, Fu X, Berisha SZ, Peng D, Nguyen TT, Liang S, Chuang CC, Cho L, Plow EF, Fox PL, Gogonea V, Tang WH, Parks JS, Fisher EA, Smith JD, Hazen SL. An abundant dysfunctional apolipoprotein A1 form in human atheroma. Nature Medicine. (2014) 20(2):193-203. PMCID: PMC3923163
- Gregory JC, Buffa JA, Org E, Wang Z, Levison BS, Zhu W, Wagner MA, Bennett BJ, Li L, DiDonato JA, Lusis AJ, Hazen SL. Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation. The Journal of Biological Chemistry. (2015) 290(9):5647-60 PMCID: PMC4342477
- Tang WHW, Wang Z, Kennedy DJ, Wu Y, Buffa J, Agatisa-Boyle B, Li XS, Levison BS, Hazen SL. The Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease. Circulation Research. (2015) 116(3):448-55 PMCID: PMC4312512
Researchers Probe Further Into Link between Red Meat and Cardiovascular Disease Risk
Dr. Hazen identified the gbu gene cluster as a potential therapeutic target for diet-associated cardiovascular disease, and showed that dietary modifications may also help reduce risk.
New Research Identifies Link Between Gut Microbes and Stroke
Drs. Hazen and Zhu found that elevated levels of blood TMAO are associated with larger infarct volume and poorer functionality following injury in preclinical stroke models, offering the first evidence that the gut microbiome directly modulates stroke severity.
New Diet-Associated Gut-Microbe Metabolite Linked to CVD
Dr. Hazen found that a metabolic byproduct of phenylalanine, called PAGln, increases risk for adverse cardiac events, and that part of beta blockers’ potent efficacy may be due to blocking the activity of this metabolite.
Study Links the Gut Microbiome and Aggressive Prostate Cancer
Dr. Sharifi and collaborators identified choline, betaine and phenylacetylglutamine as nutrients and gut microbiome metabolites associated with increased risk for lethal prostate cancer, suggesting dietary interventions may help reduce disease risk.
