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Schulman, Ira

Ira Schulman

Primary Appointment

Pharmacology

Contact Information

PO Box 800735
Charlottesville, VA 22908
Telephone: 434-924-5682
Fax: 434-982-3878
Email: igs4c@virginia.edu

Research Interests

Regulation of transcription by nuclear hormone receptors, transcriptional control of metabolism, atherosclerosis, Small molecule approaches to drug discovery

Research Description

There is a growing worldwide epidemic of metabolic disease that includes obesity, type II diabetes, high blood pressure, and cardiovascular disease. The cost of this epidemic both in human lives and in dollars is staggering. For instance, the American Heart Association estimates that over half the adults in the United States have cholesterol levels that put them at risk for the development of cardiovascular disease; the number 1 killer in the western world. While metabolic diseases have been studied for many years, the genetic networks and molecular signaling pathways that regulate metabolism and are perturbed in disease states remain to be determined. Research in our laboratory focuses on the regulation of gene expression by nuclear hormone receptors; a superfamily of DNA-binding transcription factors that activate or repress genes in response to the 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 body's 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 actually reverse established heart disease in animal models. Future studies are designed to further define the role of these receptors in controlling cardiovascular disease at the molecular level using both animal models of heart disease and in vitro systems. Currently we are employing state of the art techniques to study the regulation of metabolism genome wide. Additionally, we have initiated projects to measure gene expression in single cells. 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 is 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, inflammatory diseases and acne. The beneficial effects of drugs targeting nuclear receptors, however, are often compromised by unwanted side effects. We have developed novel approaches to identify small molecules that only control a sub-set of the genes regulated by well-studied nuclear receptor ligands. Current projects involve characterizing the activity of these new small molecules in cell culture systems and in animal models.

Selected Publications

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 LXR?, 2014; Bioorganic & medicinal chemistry letters. () PMID: 25435151 |

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

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

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

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

Zhang Y, Breevoort SR, Angdisen J, Fu M, Schmidt DR, Holmstrom SR, Kliewer SA, Mangelsdorf DJ, Schulman IG, Liver LXR? 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

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

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

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

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

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 |

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

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 |

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

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 |

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

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

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 |

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, 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 |

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

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, 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

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, 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 |