Ira G. Schulman

GetPhoto.ashx?photo=igs4c_204
  • Phone: 434-924-5682
  • Fax: 434-982-3878

Primary Appointment

Associate Professor, Pharmacology

Education

  • PhD, Baylor College of Medicine

Research Disciplines

Biochemistry, Cancer Biology, Cardiovascular Biology, Metabolism, Molecular Biology, Molecular Pharmacology

Research Interests

Regulation of transcription by nuclear hormone receptors, transcriptional control of metabolism and inflammation, small molecule approaches to drug discovery

Research Description

Understanding how gene expression is regulated in response to signals from both inside and outside the body plays a critical role in allowing us to adapt to changes in the environment. Importantly the genetic response to environmental signals is often disturbed in people with heart disease, infectious diseases, cancer, and diabetes.
Research in our laboratory focuses on the regulation of gene expression by nuclear hormone receptors; a superfamily of DNA-binding transcription factors that turn on or turn off genes in response to the direct binding of small molecules. Included in this superfamily are the well-known receptors for male and female sex hormones, however, other members of the superfamily regulate pathways that control metabolism. In particular, the liver x receptors (LXRalpha and LXRbeta) directly bind cholesterol metabolites that accumulate when cholesterol levels are high. In response to binding these ligands, LXRs regulate genes that control the bodyâs ability to transport and eliminate cholesterol. Using genetic knockouts in mice and synthetic small molecule activators we have shown that the LXRs play important roles in limiting the progression of cardiovascular disease and they can reverse established heart disease in animal models. Currently we are exploring exciting links between fat metabolism and the inflammatory response that occurs in response to alterations in diet and to infectious agents. We have also initiated projects utilizing a novel mouse model developed in the lab that allows precise control of the development of liver disease and liver. The laboratory employs a combination of state of the art techniques including genome-wide analysis of transcription, measures of gene expression in single cells, metabolite profiling and animal models of diseases. We believe that the combination of these approaches will provide an unprecedented look at regulation of gene expression in response to changes in diet and in the environment.
An exciting feature of nuclear hormone receptors in that these transcription factors were designed by nature to be regulated by the direct binding of small molecules. Not surprisingly members of the nuclear receptor superfamily are the targets of drugs used for the treatment of numerous diseases including cancer, type II diabetes, and inflammatory diseases. The beneficial effects of drugs targeting nuclear receptors, however, are often compromised by unwanted side effects. We are developing novel approaches to identify small molecules that only control a sub-set of the genes regulated by well-studied nuclear receptor ligands with the goal of identifying drugs that maintain beneficial activities while decreasing negative side effects.

Personal Statement

Understanding how gene expression is regulated in response to signals from both inside and outside the body plays a critical role in allowing us to adapt to changes in the environment. Importantly the genetic response to environmental signals is often disturbed in people with heart disease, infectious diseases, cancer, and diabetes.
Research in our laboratory focuses on the regulation of gene expression by nuclear hormone receptors; a superfamily of DNA-binding transcription factors that turn on or turn off genes in response to the direct binding of small molecules. Included in this superfamily are the well-known receptors for male and female sex hormones, however, other members of the superfamily regulate pathways that control metabolism. In particular, the liver x receptors (LXRalpha and LXRbeta) directly bind cholesterol metabolites that accumulate when cholesterol levels are high. In response to binding these ligands, LXRs regulate genes that control the bodyâs ability to transport and eliminate cholesterol. Using genetic knockouts in mice and synthetic small molecule activators we have shown that the LXRs play important roles in limiting the progression of cardiovascular disease and they can reverse established heart disease in animal models. Currently we are exploring exciting links between fat metabolism and the inflammatory response that occurs in response to alterations in diet and to infectious agents. We have also initiated projects utilizing a novel mouse model developed in the lab that allows precise control of the development of liver disease and liver. The laboratory employs a combination of state of the art techniques including genome-wide analysis of transcription, measures of gene expression in single cells, metabolite profiling and animal models of diseases. We believe that the combination of these approaches will provide an unprecedented look at regulation of gene expression in response to changes in diet and in the environment.
An exciting feature of nuclear hormone receptors in that these transcription factors were designed by nature to be regulated by the direct binding of small molecules. Not surprisingly members of the nuclear receptor superfamily are the targets of drugs used for the treatment of numerous diseases including cancer, type II diabetes, and inflammatory diseases. The beneficial effects of drugs targeting nuclear receptors, however, are often compromised by unwanted side effects. We are developing novel approaches to identify small molecules that only control a sub-set of the genes regulated by well-studied nuclear receptor ligands with the goal of identifying drugs that maintain beneficial activities while decreasing negative side effects.

Training

  • Training in the Pharmacological Sciences

Selected Publications

2024

Clark, A. T., Russo-Savage, L., Ashton, L. A., Haghshenas, N., & Schulman, I. G. (2024). A Novel Mutation in LXRα Uncovers a Role for Cholesterol Sensing in Limiting Metabolic Dysfunction-Associated Steatohepatitis (MASH).. bioRxiv. doi:10.1101/2024.05.13.593869

2022

Griffett, K., Hayes, M., Bedia-Diaz, G., Appourchaux, K., Sanders, R., Boeckman, M. P., . . . Burris, T. P. (2022). Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists. ACS CHEMICAL BIOLOGY, 17(5), 1143-1154. doi:10.1021/acschembio.2c00057

2021

Russo-Savage, L., & Schulman, I. G. (2021). Liver X receptors and liver physiology. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1867(6). doi:10.1016/j.bbadis.2021.166121

2020

Liebergall, S. R., Angdisen, J., Chan, S. H., Chang, Y., Osborne, T. F., Koeppel, A. F., . . . Schulman, I. G. (2020). Inflammation Triggers Liver X Receptor-Dependent Lipogenesis. MOLECULAR AND CELLULAR BIOLOGY, 40(2). doi:10.1128/MCB.00364-19

2019

Belorusova, A. Y., Evertsson, E., Hovdal, D., Sandmark, J., Bratt, E., Maxvall, I., . . . Lindstedt, E. -L. (2019). Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands.. Communications biology, 2(1), 431. doi:10.1038/s42003-019-0675-0

Belorusova, A. Y., Evertsson, E., Hovdal, D., Sandmark, J., Bratt, E., Maxvall, I., . . . Lindstedt, E. -L. (2019). Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands. COMMUNICATIONS BIOLOGY, 2. doi:10.1038/s42003-019-0675-0

2018

Adamson, S. E., Polanowska-Grabowska, R., Marqueen, K., Griffiths, R., Angdisen, J., Breevoort, S. R., . . . Leitinger, N. (2018). Deficiency of Dab2 (Disabled Homolog 2) in Myeloid Cells Exacerbates Inflammation in Liver and Atherosclerotic Plaques in LDLR (Low-Density Lipoprotein Receptor)-Null MiceBrief Report. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 38(5), 1020-1029. doi:10.1161/ATVBAHA.117.310467

Czimmerer, Z., Daniel, B., Horvath, A., Ruckerl, D., Nagy, G., Kiss, M., . . . Nagy, L. (2018). The Transcription Factor STAT6 Mediates Direct Repression of Inflammatory Enhancers and Limits Activation of Alternatively Polarized Macrophages. IMMUNITY, 48(1), 75-+. doi:10.1016/j.immuni.2017.12.010

2017

Schulman, I. G. (2017). Liver X receptors link lipid metabolism and inflammation. FEBS LETTERS, 591(19), 2978-2991. doi:10.1002/1873-3468.12702

Gaykema, R. P., Newmyer, B. A., Ottolini, M., Raje, V., Warthen, D. M., Lambeth, P. S., . . . Scott, M. M. (2017). Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. JOURNAL OF CLINICAL INVESTIGATION, 127(3), 1031-1045. doi:10.1172/JCI81335

2015

Fond, A. M., Lee, C. S., Schulman, I. G., Kiss, R. S., & Ravichandran, K. S. (2015). Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1. JOURNAL OF CLINICAL INVESTIGATION, 125(7), 2748-2758. doi:10.1172/JCI80300

2014

Breevoort, S. R., Angdisen, J., & Schulman, I. G. (2014). Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 34(8), 1650-+. doi:10.1161/ATVBAHA.114.303383

Ignatova, I. D., & Schulman, I. G. (2014). Liver X Receptors and Atherosclerosis It Is Not All Cholesterol. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 34(2), 242-243. doi:10.1161/ATVBAHA.113.302987

2013

Ignatova, I. D., Angdisen, J., Moran, E., & Schulman, I. G. (2013). Differential Regulation of Gene Expression by LXRs in Response to Macrophage Cholesterol Loading. MOLECULAR ENDOCRINOLOGY, 27(7), 1036-1047. doi:10.1210/me.2013-1051

Leitinger, N., & Schulman, I. G. (2013). Phenotypic Polarization of Macrophages in Atherosclerosis. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 33(6), 1120-1126. doi:10.1161/ATVBAHA.112.300173

2012

Zhang, Y., Breevoort, S. R., Angdisen, J., Fu, M., Schmidt, D. R., Holmstrom, S. R., . . . Schulman, I. G. (2012). Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. JOURNAL OF CLINICAL INVESTIGATION, 122(5), 1688-1699. doi:10.1172/JCI59817

2011

Cheng, F., Theodorescu, D., Schulman, I. G., & Lee, J. K. (2011). In vitro transcriptomic prediction of hepatotoxicity for early drug discovery. JOURNAL OF THEORETICAL BIOLOGY, 290, 27-36. doi:10.1016/j.jtbi.2011.08.009

2010

Schulman, I. G. (2010). Nuclear receptors as drug targets for metabolic disease. ADVANCED DRUG DELIVERY REVIEWS, 62(13), 1307-1315. doi:10.1016/j.addr.2010.07.002

Bischoff, E. D., Daige, C. L., Petrowski, M., Dedman, H., Pattison, J., Juliano, J., . . . Schulman, I. G. (2010). Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice.. J Lipid Res, 51(5), 900-906. doi:10.1194/jlr.M900096

Bischoff, E. D., Daige, C. L., Petrowski, M., Dedman, H., Pattison, J., Juliano, J., . . . Schulman, I. G. (2010). Non-redundant roles for LXRα and LXRβ in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. JOURNAL OF LIPID RESEARCH, 51(5), 900-906. doi:10.1194/jlr.M900096-JLR200