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Mitchell A. Lazar, MD, PhD

Mitchell A. Lazar

faculty photo
Sylvan H. Eisman Professor of Medicine
Department: Medicine

Contact information
12-102 Smilow Center for Translational Research
3400 Civic Center Boulevard / 5160
Philadelphia, PA 19104-5160
Office: (215) 898-0198
Fax: (215) 898-5408
S.B. (Chemistry)
Massachusetts Institute of Technology, 1976.
Ph.D. (Neuroscience)
Stanford Univerity, 1981.
Stanford Univerity, 1982.
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Description of Research Expertise

Research Interests
Epigenomic regulation of transcription and metabolism by nuclear receptors; mechanism of obesity-associated insulin resistance and diabetes; circadian regulation of metabolism

Key words: diabetes, endocrinology, epigenomics, nuclear receptors, circadian rhythms

Description of Research
The Lazar laboratory is studying the transcriptional regulation of metabolism. We are particularly focused on the role played by nuclear receptors (NRs). In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors by recruiting corepressor complexes that include the chromatin modulating enzyme histone deacetylase 3 (HDAC3). We are studying the tissue-specific and physiological roles of the corepressor complexes using by combining genomic, genetic, proteomic, bioinformatic, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erb alpha, which utilizes the corepressor complex to potently repress transcription. Rev-erb alpha is a key repressive component of the circadian clock that coordinates metabolism and biological rhythms. We are also studying PPAR gamma, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPAR gamma have potent antidiabetic activity, and thus PPAR gamma represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mice and humans. We also have discovered resistin, a novel hormone and target of PPAR gamma that is made by fat cells in rodents and by macrophages in humans, and are testing the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.

Rotation Projects for 2015-2016
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
David Steger, Ph.D. (Research Assistant Professor)
Bin Fang, Ph.D. (Post-doc)
Sean Armour, Ph.D. (Post-doc)
Romeo Papazyan, Ph.D. (Post-doc)
Satoshi Yoshino, Ph.D. (Post-doc)
Victoria Nelson, Ph.D. (Post-doc)
Dongyin Guan, Ph.D. (Post-doc)
Matthew Emmett (Graduate Student)
Jarrett Remsberg (Graduate Student)
Yuxiang Zhang (Graduate Student)
Yong Hoon Kim (Graduate Student)
Erika Briggs (Research Specialist)
Lindsey Peed(Research Specialist)
Manashree Damle (Bioinformatics Research Specialist)
Yee Hoon Foong (Research Specialist)
Wesley Ho (Research Specialist)
Joe Weaver (Lab Manager)

Selected Publications

Gerhart-Hines Z, Lazar MA.: Rev-erbα and the circadian transcriptional regulation of metabolism. Diabetes Obes Metab. Suppl 1: 12-6, Sept 2015 Notes: doi: 10.1111/dom.12510. PMID:26332963[PubMed - in process] PMCID: PMC4562061 [Available on 2016-09-01]

Fang B, Lazar MA.: Dissecting the Rev-erbα Cistrome and the Mechanisms Controlling Circadian Transcription in Liver. Cold Spring Harb Symp Quant Biol. Page: pii: 027508. [Epub ahead of print] Sept 2015 Notes: PMID: 26370410

Altman BJ, Hsieh AL, Sengupta A, Krishnanaiah SY, Stine ZE, Walton ZE, Gouw AM, Venkataraman A, Li B, Goraksha-Hicks P, Diskin SJ, Bellovin DI, Simon MC, Rathmell JC, Lazar MA, Maris JM, Felsher DW, Hogenesch JB, Weljie AM, Dang CV.: MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell Metab Sept 2015 Notes: pii: S1550-4131(15)00460-X. doi: 10.1016/j.cmet.2015.09.003. [Epub ahead of print]

Soccio RE, Chen ER, Rajapurkar SR, Safabakhsh P, Marinis JM, Dispirito JR, Emmett MJ, Briggs ER, Fang B, Everett LJ, Lim HW, Won KJ, Steger DJ, Wu Y, Civelek M, Voight BF, Lazar MA.: Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo. Cell 162(1): 33-44, Jul 2015 Notes: doi: 10.1016/j.cell.2015.06.025. PMID: 26140591

Lim HW, Uhlenhaut NH, Rauch A, Weiner J, Hübner S, Hübner N, Won KJ, Lazar MA, Tuckermann J, Steger DJ.: Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res. 25(6): 836-44, Jun 2015 Notes: doi: 10.1101/gr.188581.114. Epub 2015 May 8.

Cohen DM, Won KJ, Nguyen N, Lazar MA, Chen CS, Steger DJ.: ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis. Elife Jun 2015 Notes: doi: 10.7554/eLife.06821. PMID: 26111340.

Yuxiang Zhang, Bin Fang, Matthew J. Emmett, Manashree Damle, Zheng Sun, Dan Feng, Sean M. Armour, Jarrett R. Remsberg, Jennifer Jager, Raymond E. Soccio, David J. Steger, Mitchell A. Lazar : Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock. Science 348(6242): 1488-92, Jun 2015.

Gerhart-Hines Z, Lazar MA.: Circadian metabolism in the light of evolution. Endocr Rev. 36(3): 289-304, Jun 2015 Notes: doi: 10.1210/er.2015-1007. Epub 2015 Apr 30.

Harms MJ, Lim HW, Ho Y, Shapira SN, Ishibashi J, Rajakumari S, Steger DJ, Lazar MA, Won KJ, Seale P.: PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program. Genes Dev. 29(3): 298-307, Feb 2015.

Jang JC, Chen G, Wang SH, Barnes MA, Chung JI, Camberis M, Le Gros G, Cooper PJ, Steel C, Nutman TB, Lazar MA, Nair MG.: Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden. PLoS Pathog. 11(1:e1004579), Jan 2015 Notes: doi: 10.1371/journal.ppat.1004579. eCollection 2015 Jan.

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Last updated: 09/24/2015
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