Seminar

PAS signaling in health and disease

Prof. Christopher Bradfield

Research Interests: Signal Transduction of PAS proteins. Mechanisms of environmental sensing. Use  of mouse and yeast genetics to understand toxicant signal transduction pathways. Toxicology of dioxins, PCBs and PAHs by Ah receptor and ARNT. Milestones 2002-MERIT R37 – Understanding the significance and role of the family of transcriptional regulators known as PAS proteins, which control a number of processes including xenobiotic metabolism, circadian rhythms, angiogenesis, and neurogenesis Patents 1992 – Assay for dioxins 1997 – Biological assay for detecting agonists to the Ah receptor Research Our laboratory is interested in the biology of environmental sensing. We currently focus on a family of transcriptional regulators known as PAS proteins. Members of this emerging family of proteins control a number of processes, including xenobiotic metabolism (Ah-receptor and ARNT), circadian rhythms (MOP3, MOP4, CLOCK and PER), hypoxia signaling and angiogenesis (HIF1a, HIF2a, HIF3a, ARNT, ARNT2 and MOP3), and neurogenesis (SIM1 and SIM2). One model system that is currently emphasized is the signal transduction pathway mediated by Ah-receptor/Arnt heterodimeric complex. These helix-loop-helix-PAS proteins regulate the induction of a number of xenobiotic metabolizing enzymes that occur in response to exposure to a variety of polycyclic aromatic environmental pollutants. In addition, the Ah-receptor mediates a second battery of genes responsible for a number of “toxic effects” of dioxins, such as epithelial hyperplasia, immunosuppression, teratogenesis, and tumor promotion. To understand these proteins and their signal transduction pathways, we take advantage of genetically manipulable organisms such as mice and yeast. We use yeast genetics as a method to identify genes that are required for signaling. The yeast system is particularly valuable in modifier screens to identify novel components of the PAS signaling pathways. Experiments in the murine system help us to understand the physiological function of these proteins. Current areas of interest include the use of gene-targeting to generate informative bHLH-PAS loci and the use of more classical transgenic approaches to construct murine models that will help us characterize the mechanisms that underlie the toxicological and developmental effects of halogenated aromatics like dioxin.