Ira G. Schulman

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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

Russo-Savage L., Schulman I. G., Liver X receptors and liver physiology, 2021; Biochim Biophys Acta Mol Basis Dis. 1867(6) 166121. PMID:

Liebergall S. R., Angdisen J., Chan S. H., Chang Y., Osborne T. F., Koeppel A. F., Turner S. D., Schulman I. G., Inflammation Triggers Liver X Receptor-Dependent Lipogenesis, 2020; Mol Cell Biol. 40(2) . PMID:

Belorusova A. Y., Evertsson E., Hovdal D., Sandmark J., Bratt E., Maxvall I., Schulman I. G., Akerblad P., Lindstedt E. L., Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands, 2019; Commun Biol. 2() 431. PMID:

Adamson S. E., Polanowska-Grabowska R., Marqueen K., Griffiths R., Angdisen J., Breevoort S. R., Schulman I. G., Leitinger N., Deficiency of Dab2 (Disabled Homolog 2) in Myeloid Cells Exacerbates Inflammation in Liver and Atherosclerotic Plaques in LDLR (Low-Density Lipoprotein Receptor)-Null Mice, 2018; Arterioscler Thromb Vasc Biol. 38() 1020-1029. PMID: | PMCID: 29599136

Schulman I. G., Liver X receptors link lipid metabolism and inflammation, 2017; FEBS Lett. 591(19) 2978-2991. PMID:

Gaykema R. P., Newmyer B. A., Ottolini M., Raje V., Warthen D. M., Lambeth P. S., Niccum M., Yao T., Huang Y., Schulman I. G., Harris T. E., Patel M. K., Williams K. W., Scott M. M., Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight, 2017; J Clin Invest. 127(3) 1031-1045. PMID:

Kick E. K., Busch B. B., Martin R., Stevens W. C., Bollu V., Xie Y., Boren B. C., Nyman M. C., Nanao M. H., Nguyen L., Plonowski A., Schulman I. G., Yan G., Zhang H., Hou X., Valente M. N., Narayanan R., Behnia K., Rodrigues A. D., Brock B., Smalley J., Cantor G. H., Lupisella J., Sleph P., Grimm D., Ostrowski J., Wexler R. R., Kirchgessner T., Mohan R., Discovery of Highly Potent Liver X Receptor beta Agonists, 2016; ACS Med Chem Lett. 7(12) 1207-1212. PMID:

Fond A. M., Lee C. S., Schulman I. G., Kiss R. S., Ravichandran K. S., Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1, 2015; J Clin Invest. 125(7) 2748-58. PMID:

Ignatova ID, Schulman IG, Liver X receptors and atherosclerosis: it is not all cholesterol., 2014; Arteriosclerosis, thrombosis, and vascular biology. 34(2) 242-3. PMID: 24431422 | PMCID: PMC3966182

Breevoort SR, Angdisen J, Schulman IG, Macrophage-independent regulation of reverse cholesterol transport by liver X receptors., 2014; Arteriosclerosis, thrombosis, and vascular biology. 34(8) 1650-60. PMID: 24947527 | PMCID: PMC4107336

Kick E, Martin R, Xie Y, Flatt B, Schweiger E, Wang TL, Busch B, Nyman M, Gu XH, Yan G, Wagner B, Nanao M, Nguyen L, Stout T, Plonowski A, Schulman I, Ostrowski J, Kirchgessner T, Wexler R, Mohan R, Liver X Receptor (LXR) partial agonists: Biaryl pyrazoles and imidazoles displaying a preference for LXRβ, 2014; Bioorganic & medicinal chemistry letters. () . PMID: 25435151

Ignatova ID, Angdisen J, Moran E, Schulman IG, Differential regulation of gene expression by LXRs in response to macrophage cholesterol loading., 2013; Molecular endocrinology (Baltimore, Md.). 27(7) 1036-47. PMID: 23686114 | PMCID: PMC3706843

Leitinger N, Schulman IG, Phenotypic polarization of macrophages in atherosclerosis., 2013; Arteriosclerosis, thrombosis, and vascular biology. 33(6) 1120-6. PMID: 23640492 | PMCID: PMC3745999

Zhang Y, Breevoort SR, Angdisen J, Fu M, Schmidt DR, Holmstrom SR, Kliewer SA, Mangelsdorf DJ, Schulman IG, Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice., 2012; The Journal of clinical investigation. 122(5) 1688-99. PMID: 22484817 | PMCID: PMC3336978

Cheng F, Theodorescu D, Schulman IG, Lee JK, In vitro transcriptomic prediction of hepatotoxicity for early drug discovery., 2011; Journal of theoretical biology. 290() 27-36. PMID: 21884709 | PMCID: PMC3386613

Huang HJ, Schulman IG, Regulation of metabolism by nuclear hormone receptors., 2010; Progress in molecular biology and translational science. 87() 1-51. PMID: 20374700

Bischoff ED, Daige CL, Petrowski M, Dedman H, Pattison J, Juliano J, Li AC, Schulman IG, Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice., 2010; Journal of lipid research. 51(5) 900-6. PMID: 20388921 | PMCID: PMC2853457

Schulman IG, Nuclear receptors as drug targets for metabolic disease., 2010; Advanced drug delivery reviews. 62(13) 1307-15. PMID: 20655343 | PMCID: PMC2987515

Flatt B, Martin R, Wang TL, Mahaney P, Murphy B, Gu XH, Foster P, Li J, Pircher P, Petrowski M, Schulman I, Westin S, Wrobel J, Yan G, Bischoff E, Daige C, Mohan R, Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR)., 2009; Journal of medicinal chemistry. 52(4) 904-7. PMID: 19159286

Schulman IG, Cholesterol worships a new idol., 2009; Journal of molecular cell biology. 1(2) 75-6. PMID: 19783832

Schulman IG, Heyman RA, The flip side: Identifying small molecule regulators of nuclear receptors., 2004; Chemistry & biology. 11(5) 639-46. PMID: 15157874

Li J, Pircher PC, Schulman IG, Westin SK, Regulation of complement C3 expression by the bile acid receptor FXR., 2004; The Journal of biological chemistry. 280(9) 7427-34. PMID: 15590640

Willy PJ, Murray IR, Qian J, Busch BB, Stevens WC, Martin R, Mohan R, Zhou S, Ordentlich P, Wei P, Sapp DW, Horlick RA, Heyman RA, Schulman IG, Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand., 2004; Proceedings of the National Academy of Sciences of the United States of America. 101(24) 8912-7. PMID: 15184675 | PMCID: PMC428446

Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM, Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle., 2004; Proceedings of the National Academy of Sciences of the United States of America. 101(17) 6570-5. PMID: 15100410 | PMCID: PMC404086

Levin N, Bischoff ED, Daige CL, Thomas D, Vu CT, Heyman RA, Tangirala RK, Schulman IG, Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists., 2004; Arteriosclerosis, thrombosis, and vascular biology. 25(1) 135-42. PMID: 15539622

Pircher PC, Kitto JL, Petrowski ML, Tangirala RK, Bischoff ED, Schulman IG, Westin SK, Farnesoid X receptor regulates bile acid-amino acid conjugation., 2003; The Journal of biological chemistry. 278(30) 27703-11. PMID: 12754200

Wagner BL, Valledor AF, Shao G, Daige CL, Bischoff ED, Petrowski M, Jepsen K, Baek SH, Heyman RA, Rosenfeld MG, Schulman IG, Glass CK, Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression., 2003; Molecular and cellular biology. 23(16) 5780-9. PMID: 12897148 | PMCID: PMC166346

Tangirala RK, Bischoff ED, Joseph SB, Wagner BL, Walczak R, Laffitte BA, Daige CL, Thomas D, Heyman RA, Mangelsdorf DJ, Wang X, Lusis AJ, Tontonoz P, Schulman IG, Identification of macrophage liver X receptors as inhibitors of atherosclerosis., 2002; Proceedings of the National Academy of Sciences of the United States of America. 99(18) 11896-901. PMID: 12193651 | PMCID: PMC129365

Muscat GE, Wagner BL, Hou J, Tangirala RK, Bischoff ED, Rohde P, Petrowski M, Li J, Shao G, Macondray G, Schulman IG, Regulation of cholesterol homeostasis and lipid metabolism in skeletal muscle by liver X receptors., 2002; The Journal of biological chemistry. 277(43) 40722-8. PMID: 12193599

Osburn DL, Shao G, Seidel HM, Schulman IG, Ligand-dependent degradation of retinoid X receptors does not require transcriptional activity or coactivator interactions., 2001; Molecular and cellular biology. 21(15) 4909-18. PMID: 11438648 | PMCID: PMC87210

Shao G, Heyman RA, Schulman IG, Three amino acids specify coactivator choice by retinoid X receptors., 2000; Molecular endocrinology (Baltimore, Md.). 14(8) 1198-209. PMID: 10935544

Schulman IG, Shao G, Heyman RA, Transactivation by retinoid X receptor-peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimers: intermolecular synergy requires only the PPARgamma hormone-dependent activation function., 1998; Molecular and cellular biology. 18(6) 3483-94. PMID: 9584188 | PMCID: PMC108929

Schulman IG, Evans RM, Retinoid receptors in development and disease., 1997; Leukemia. 11() 376-7. PMID: 9209395

Schulman IG, Li C, Schwabe JW, Evans RM, The phantom ligand effect: allosteric control of transcription by the retinoid X receptor., 1997; Genes & development. 11(3) 299-308. PMID: 9030683

Chakravarti D, LaMorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, Evans RM, Role of CBP/P300 in nuclear receptor signalling., 1996; Nature. 383(6595) 99-103. PMID: 8779723

Schulman IG, Juguilon H, Evans RM, Activation and repression by nuclear hormone receptors: hormone modulates an equilibrium between active and repressive states., 1996; Molecular and cellular biology. 16(7) 3807-13. PMID: 8668198 | PMCID: PMC231377

Lala DS, Mukherjee R, Schulman IG, Koch SS, Dardashti LJ, Nadzan AM, Croston GE, Evans RM, Heyman RA, Activation of specific RXR heterodimers by an antagonist of RXR homodimers., 1996; Nature. 383(6599) 450-3. PMID: 8837780

Schulman IG, Chakravarti D, Juguilon H, Romo A, Evans RM, Interactions between the retinoid X receptor and a conserved region of the TATA-binding protein mediate hormone-dependent transactivation., 1995; Proceedings of the National Academy of Sciences of the United States of America. 92(18) 8288-92. PMID: 7667283 | PMCID: PMC41142

Schulman IG, Bloom K, Genetic dissection of centromere function., 1993; Molecular and cellular biology. 13(6) 3156-66. PMID: 8497246 | PMCID: PMC359754

Schulman I, Bloom KS, Centromeres: an integrated protein/DNA complex required for chromosome movement., 1991; Annual review of cell biology. 7() 311-36. PMID: 1809349