PO Box 800735
Charlottesville, VA 22908
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 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.