Dr. Simon Hirota

Biography

Throughout my research training I have studied a variety of organ systems, including the vascular system and the respiratory and gastrointestinal tracts.  I was first trained as a smooth muscle electrophysiologist, assessing ion currents and calcium signals in vascular and airway smooth muscle, in the context of hypertension and asthma, respectively. I began specialized training in the gastrointestinal tract as a post-doctoral fellow.  Originally recruited to assess gastrointestinal motility in the context of intestinal inflammation, I began to pursue studies focused on the regulation of intestinal epithelial barrier function and mucosal immune signaling in the context of the inflammatory bowel diseases (IBD) and infectious colitis.  To this end, I published a series of papers assessing the innate immune responses involved in C. difficile toxin-associated tissue damage and was among the first groups to report on the functional role of the NLRP3 inflammasome in the pathogenesis of IBD.  The complete study, published in the IBD Journal, has been cited 390 times since 2011.  In addition to my contributions in the gastrointestinal tract, my expertise in inflammasome biology allowed for fruitful collaborations with groups working on inflammatory diseases of the liver, kidney and cardiovascular system. 

My laboratory’s current research interests lie in the mechanisms that govern optimal gastrointestinal health through the maintenance of intestinal mucosal homeostasis, in the context of infectious colitis and IBD.  We focus on host-microbe/host-pathogen interactions at the intestinal epithelium and how these processes contribute to optimal gut health, and how aberrant interactions contribute to the pathophysiology of IBD and infectious colitis.  Enhanced intestinal epithelial permeability is observed in a number of gastrointestinal pathologies, including the IBD, and during acute infectious colitis (e.g., C. difficile colitis).  Thus, I am interested in the systems that regulate the intestinal epithelium and preserve barrier function through enhancing epithelial cell survival, maintaining cell-cell contacts and regulating epithelial wound healing. To this end, my laboratory is focused on the role that nuclear receptors play in host-microbe/host-pathogen/host-environment interactions in the gastrointestinal tract.  I believe that nuclear receptors act as xenobiotic sensors and respond to environmental contaminants, microbial metabolites and other small molecules, and regulate cellular processes in intestinal epithelial cells and mucosal immune cells.  We are currently directing our efforts to understand how the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both xenobiotic/endobiotic sensors that regulate the body’s detoxification responses, contribute to the regulation of intestinal mucosal homeostasis, host-defense, tissue repair and the regulation of fibrosis. In other studies, my laboratory is examining the role that NR4A1 (an orphan nuclear receptor also known as NUR77, TR3, NGFI-B, or NAK-1) plays in regulating intestinal epithelial barrier function, mucosal repair responses and intestinal fibrosis, to determine whether it could be an attractive therapeutic target for treating gastrointestinal diseases associated with mucosal damage, increased permeability and aberrant tissue remodeling.