Stanley Hazen Laboratory

Research

Overview

A long term goal of my laboratory is to understand mechanisms through which inflammation contributes to diseases like atherosclerosis and chronic kidney disease. Several major research programs are currently under investigation. One research program focuses on the role of the gut microbiome in cardiovascular, kidney and metabolic diseases. A second area focuses on development of novel therapeutic approaches to the treatment of residual cardiovascular disease risks, kidney and metabolic disorders.  

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, and human clinical investigations.  A major emphasis is the combined use of large scale clinical studies to define hypotheses, and development of therapeutic interventions for the treatment of disorders.

Experimental Data

Experimental data and computational models for downloading

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:

a) All-atom molecular model of the Solar Flares model of nascent HDL. 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:

	a) Small angle neutron scattering intensities for the protein component of nascent HDL (12 % D2O, collected at the Institute Laue-Langevin, Grenoble, France).
	b) 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).
	c) Small angle neutron scattering intensities for the lipid component of nascent HDL (42 % D2O, collected at the Institute Laue-Langevin, Grenoble, France).
	d) 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).
	e) The Double Super Helix model of nascent HDL. 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:

	a) Small angle neutron scattering intensities for the protein component of nascent HDL (12 % D2O, collected at the Jülich Center for Neutron Science, Garching, Germany).
	b) The solution low-resolution structure of the protein component of nascent HDL obtained by small angle neutron scattering with contrast variation (12 % D2O, JCNS data).
	Mirror image of the solution low-resolution structure of the protein component of nascent HDL.
	c) Small angle neutron scattering intensities for the lipid component of nascent HDL (42 % D2O, collected at the Jülich Center for Neutron Science, Garching, Germany).
	d) The solution low-resolution structure of the lipid component of nascent HDL obtained by small angle neutron scattering with contrast variation (42 % D2O, JCNS data, PDB file)
	e) Molecular model of nascent HDL obtained after 60 ns molecular dynamics simulation of the Double Super Helix model.
	f) Hydrogen-deuterium exchange data (HD incorporation factors, residue unfolding constants, HD exchange rate constants) calculated from the molecular dynamics simulation trajectory of the Double Super Helix model (excel format).

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:

	a) Small angle neutron scattering intensities for the protein component of spherical HDL (12 % D2O).
	b) The solution low-resolution structure of the protein component of spherical HDL obtained by small angle neutron scattering with contrast variation (12 % D2O).
	c) Small angle neutron scattering intensities for the lipid component of spherical HDL (42 % D2O).
	d) The solution low-resolution structure of the lipid component of spherical HDL obtained by small angle neutron scattering with contrast variation (42 % D2O).

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:

	a) Small angle neutron scattering intensities for the protein component of nascent HDL/DMPC (12 % D2O).
	b) The solution low-resolution structure of the protein component of nascent HDL/DMPC obtained by small angle neutron scattering with contrast variation (12 % D2O).
	c) Small angle neutron scattering intensities for the lipid component of nascent HDL/DMPC (42 % D2O).
	d) The solution low-resolution structure of the lipid component of nascent HDL/DMPC obtained by small angle neutron scattering with contrast variation (42 % D2O).
	e) Molecular model of nascent HDL/DMPC obtained from the low resolution structures of the protein and lipid components of nascent HDL/DMPC (PDB file).
	f) Small angle neutron scattering intensities for the protein component of nascent HDL/DMPC+Chol (12 % D2O).
	g) The solution low-resolution structure of the protein component of nascent HDL/DMPC+Chol obtained by small angle neutron scattering with contrast variation (12 % D2O).
	h) Small angle neutron scattering intensities for the lipid component of nascent HDL/DMPC+Chol (42 % D2O).
	i) The solution low-resolution structure of the lipid component of nascent HDL/DMPC+Chol obtained by small angle neutron scattering with contrast variation (42 % D2O).

Selected Publications

View publications for Stanley Hazen, MD, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)

1. 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
2. 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
3. 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
4. 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
5.  Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell. 2015;163(7):1585-95. Epub 2015/12/22. doi: 10.1016/j.cell.2015.11.055. PubMed PMID: 26687352; PMCID: PMC4871610. 
6. Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WHW, DiDonato JA, Brown JM, Lusis AJ, Hazen SL. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016;165(1):111-24. Epub 2016/03/15. doi: 10.1016/j.cell.2016.02.011. PubMed PMID: 26972052; PMCID: PMC4862743.
7. Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, Funabashi M, Ramer-Tait AE, Naga Prasad SV, Fiehn O, Rey FE, Tang WHW, Fischbach MA, DiDonato JA, Hazen SL. A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. Cell. 2020;180(5):862-77.e22. Epub 2020/03/07. doi: 10.1016/j.cell.2020.02.016. PubMed PMID: 32142679; PMCID: PMC7402401.
8. Buffa JA, Romano KA, Copeland MF, Cody DB, Zhu W, Galvez R, Fu X, Ward K, Ferrell M, Dai HJ, Skye S, Hu P, Li L, Parlov M, McMillan A, Wei X, Nemet I, Koeth RA, Li XS, Wang Z, Sangwan N, Hajjar AM, Dwidar M, Weeks TL, Bergeron N, Krauss RM, Tang WHW, Rey FE, DiDonato JA, Gogonea V, Gerberick GF, Garcia-Garcia JC, Hazen SL. The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism. Nat Microbiol. 2022;7(1):73-86. Epub 2021/12/25. doi: 10.1038/s41564-021-01010-x. PubMed PMID: 34949826; PMCID: PMC8732312.
9. Zhu Y, Dwidar M, Nemet I, Buffa JA, Sangwan N, Li XS, Anderson JT, Romano KA, Fu X, Funabashi M, Wang Z, Keranahalli P, Battle S, Tittle AN, Hajjar AM, Gogonea V, Fischbach MA, DiDonato JA, Hazen SL. Two distinct gut microbial pathways contribute to meta-organismal production of phenylacetylglutamine with links to cardiovascular disease. Cell Host Microbe. 2023;31(1):18-32.e9. Epub 20221221. doi: 10.1016/j.chom.2022.11.015. PubMed PMID: 36549300; PMCID: PMC9839529.
10. Saha PP, Gogonea V, Sweet W, Mohan ML, Singh KD, Anderson JT, Mallela D, Witherow C, Kar N, Stenson K, Harford T, Fischbach MA, Brown JM, Karnik SS, Moravec CS, DiDonato JA, Naga Prasad SV, Hazen SL. Gut microbe-generated phenylacetylglutamine is an endogenous allosteric modulator of β2-adrenergic receptors. Nature Commun. 2024 Aug 6;15(1):6696. doi: 10.1038/s41467-024-50855-3. PMID: 39107277; PMCID: PMC11303761.