Ira G. Schulman
- PhD, Baylor College of Medicine
- Associate Professor, Pharmacology
- Phone: 434-924-5682
- Email: firstname.lastname@example.org
Regulation of transcription by nuclear hormone receptors, transcriptional control of metabolism, atherosclerosis, Small molecule approaches to drug discovery
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 pathological states remain to be determined.
Research in the laboratory focuses on the analysis 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 development of cardiovascular disease. Future studies are designed to further define the role of these receptors in controlling cardiovascular disease at the molecular level. We are especially interested in the differences between the two iso-types of LXR. LXRalpha appears to be a strong activator of transcription while LXRbeta functions better as a repressor.
Many biological pathways are controlled by dynamic interactions between proteins. In the case of nuclear hormone receptors, protein-protein interactions provide the critical link between receptors and the transcriptional machinery. A second interest of the laboratory is to develop novel chemical reagents that disrupt protein-protein interactions. We anticipate that such small molecules will serve as tools help to unravel important biological pathways and may provide improved therapeutic reagents for the treatment of cancer and metabolic disease.
- Breevoort S, Angdisen J, Schulman I. Macrophage-independent regulation of reverse cholesterol transport by liver X receptors. Arteriosclerosis, thrombosis, and vascular biology. 2014;34(8): 1650-60. PMID: 24947527 | PMCID: PMC4107336
- Ignatova I, Schulman I. Liver X receptors and atherosclerosis: it is not all cholesterol. Arteriosclerosis, thrombosis, and vascular biology. 2014;34(2): 242-3. PMID: 24431422 | PMCID: PMC3966182
- Ignatova I, Angdisen J, Moran E, Schulman I. Differential regulation of gene expression by LXRs in response to macrophage cholesterol loading. Molecular endocrinology (Baltimore, Md.). 2013;27(7): 1036-47. PMID: 23686114 | PMCID: PMC3706843
- Leitinger N, Schulman I. Phenotypic polarization of macrophages in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2013;33(6): 1120-6. PMID: 23640492 | PMCID: PMC3745999
- Cheng F, Theodorescu D, Schulman I, Lee J. In vitro transcriptomic prediction of hepatotoxicity for early drug discovery. Journal of theoretical biology. 2011;290 27-36. PMID: 21884709 | PMCID: PMC3386613
- Nuclear receptors as drug targets for metabolic disease. Advanced drug delivery reviews. 2010;62(13): 1307-15. PMID: 20655343 | PMCID: PMC2987515
- Bischoff E, Daige C, Petrowski M, Dedman H, Pattison J, Juliano J, Li A, Schulman I. Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. Journal of lipid research. 2010;51(5): 900-6. PMID: 20388921 | PMCID: PMC2853457
- Cholesterol worships a new idol. Journal of molecular cell biology. 2009;1(2): 75-6. PMID: 19783832