Host-Microbiome Crosstalk: Discovery of Mechanisms and New Microbes
Orphan nuclear receptors (those that lack a well defined physiologic ligand) control nearly every major physiologic and biochemical process in eukaryotes - cell metabolism (e.g., cholesterol, energy, bile acids), xenobiotic detoxification, cell differentiation (e.g., gastrulation, retinal development), circadian rhythm, and cancer cell growth and apoptosis (e.g., NURR77). Of these receptors, the steroid and xenobiotic receptor (SXR) is a key regulator of genes encoding drug metabolizing and transport proteins. In addition, SXR has been implicated in cancer drug resistance, carcinogenesis, innate immunity, infection control and pathophysiologic states like osteomalacia. Our laboratory focuses on defining the role of SXR and other orphans by using novel and dynamic models of human pathophysiology in (i) xenobiotic metabolism and pharmacology; (ii) carcinogenesis, organogenesis and anticancer drug resistance and (iii) innate immunity.
Recently, our laboratory has directed interests in the mammalian microbiome. We have discovered a novel link between the microbial metabolome and orphan nuclear receptor, SXR/PXR in the intestines (Immunity, 2014). Further work in the laboratory is focussed on defining how the microbial environment shapes health and disease. The overall theme of our research going forward is to understand the mechanistic basis of host immune system and its regulation by gut microbiota through their secretion of small molecule metabolites and/or proteins. The techniques and methodologies used in our laboratory involve use and generation of genetic mouse models, study of bacterial phenotypes using classical and translational microbiology, DNA/RNA sequencing, cell, molecular and proteomic technologies. It is hoped that through such investigation we will discover new therapeutic leads for diseases such as inflammatory bowel disease and colon cancer.