PO Box 800735
Charlottesville, VA 22908
Regulation of transcription by nuclear hormone receptors, transcriptional control of metabolism and inflammation, small molecule approaches to drug discovery
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 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. Currently we are exploring exciting links between fat metabolism and the inflammatory response that occurs in response to infectious agents. We have also initiated new projects exploring the susceptibility of cancer cells to changes in cholesterol and fat metabolism. 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.