Digestive system

The research focus of my lab focuses on the molecular mechanisms underlying normal and pre-neoplastic epithelial cell growth in the luminal gastrointestinal tract. My recent studies involve the use of animal and cell culture models to dissect the pathways through which chronic inflammatory processes, generally from bacterial colonization, leads to mucosal alterations of the luminal GI tract sets the stage for neoplastic transformation (pre-neoplasia). Ongoing projects in my laboratory include the role of sonic hedgehog in gastric homeostasis, e.g., acid secretion and chronic gastritis leading to metaplasia/dysplasia; the role of the nuclear protein menin in the genesis of neuroendocrine tumors, e.g., gastrinomas, carcinoids, and the role of the Krüppel-like transcription factor ZBP-89 (ZNF148) in mucosal restitution from infection to neoplastic transformation. We have used mouse models to dissect the role of Hedgehog signaling in the stomach during chronic inflammation. Over the past 18 years, my lab has established a major role for Hedgehog signaling in normal gastric physiology and during gastric preneoplasia. My initial studies demonstrated that parietal cells and therefore acid secretion requires sonic hedgehog signaling. More recently, studies from my lab have revealed that myeloid-derived suppressor cells (MDSCs) require Hedgehog signaling to create a permissive environment that supports the development of gastric metaplasia, a mucosal lesion preceding cancer.

The innate immune system has a large repertoire of receptors/sensors that respond to microbial components and host “danger signals” in order to regulate inflammation and immune responses. The dysregulation of many of these sensors has been linked to chronic inflammatory disorders (e.g., inflammatory bowel diseases) and multiple types of cancer. My group’s research focuses on how the dynamic relationship between the intestinal microbiota and these innate immune sensors regulate the cell signaling events driving chronic inflammation and cancer development. We seek to treat these diseases through the manipulation of intestinal microbial ecology and redirection of immune activation.

Jean M. Wilson, Ph.D. is a Professor of Cellular and Molecular Medicine at the University of Arizona and member of the Arizona Cancer Center. Dr. Wilson’s work focuses on the establishment and maintenance of the mucosal barrier of the intestine. The cells of the intestine provide a selective barrier to pathogens and toxins, and loss of this barrier function is fundamental to pathologies such as inflammatory bowel disease and bacterial infection. In addition, loss of cellular interactions important for barrier function may predispose these cells to cancer. Work in Dr. Wilson’s laboratory focuses on a protein that is highly expressed in developing intestine, implying a critical role in the formation of the intestinal epithelium. Disruption of this protein compromises junctional integrity and epithelial polarity. Furthermore, expression of this protein is decreased in a model of neonatal necrotizing enterocolitis, a disease of newborns with high morbidity and mortality. These findings implicate this protein in the maintenance of intestinal barrier function in the neonate. In addition, continued expression in the adult intestine positions it to regulate epithelial permeability and polarity throughout life. Our studies focus on protein partners that interact with this protein with the goal of identifying the molecular machinery that regulates this pathway.

Melissa Herbst-Kralovetz, PhD is an Associate Professor in the Departments of Basic Medical Sciences and Obstetrics and Gynecology and is Director of the Women's Health Microbiome Initiative at the UA College of Medicine-Phoenix. The Herbst-Kralovetz research lab is broadly interested in understanding innate mucosal immune responses to resident bacteria, pathogens (e.g HSV-2), and microbial products at mucosal sites, including the female reproductive tract. The mucosa provides a major immune barrier (physical, biological, and chemical) to microbial insult and her lab is interested in studying the mucosal barrier function of the lower female reproductive tract and its role in host defense against infection and inflammation as well as maintaining mucosal homeostasis. Dr. Herbst-Kralovetz has a long-standing interest and background in studying infections/conditions that impact women’s health.

An overwhelming obesogenic environment, the backdrop to a globally-expanding western lifestyle, has led to a ‘diabesity’ pandemic that represents a costly and urgent global health crisis. The success of gastric bypass surgery and gut-derived diabetes/obesity treatments highlight the major role of the gastrointestinal (GI) tract in metabolic diseases. My research aims to better understand the complex intestinal signaling mechanisms involved in the regulation of energy and glucose homeostasis in physiological and pathophysiological states. My work to date has focused on elucidating how nutrients are sensed by the gut, and how changes in these mechanisms lead to a reduction in food intake and/or a reduction in endogenous hepatic glucose production via a gut-brain neuronal axis. More specifically, my work focused on alterations in intestinal detection of fats and carbohydrates and paracrine gut peptide signaling (CCK and GLP-1) during high-fat feeding, the influence of the gut microbiota on these pathways, and how these contribute to the development of obesity and diabetes. As such, I plan to continue to decipher this complex interaction between gut-sensing mechanisms and the gut microbiota, as a better understanding of these pathways are crucial for the development of successful, gut-targeted therapeutic options in the treatment of metabolic diseases. Given the rapid rise of obesity/diabetes in only several generations, obesity cannot be attributed to genomic alterations, but more likely results from a complex set of interactions between genetic risk factors and environmental changes. Importantly, studies suggest the development of adult phenotypes (obesity and diabetes) results from early, transient environmental interactions, coined ‘early life programming,’ which has been partly attributed to epigenetic changes. Gut microbiota development is also crucial during this time, and differing modes of development (i.e. maternal microbiota, type of delivery, breastfeeding vs. formula feeding, etc.) can lead to later metabolic dysfunctions. Therefore, using animals models prone to the development of obesity and/or diabetes from polygenetic inheritance and transgenerational, epigenetic, changes in gene activity, I am studying how varying environmental factors (diet, housing, exercise, pre/post-natal environment, etc.) result in differential effects on the gut microbiota, intestinal nutrient sensing, and whole body energy and glucose homeostasis. A better understanding of how early changes in the gut microbiota can impact the development of metabolic regulation, and vice versa, is vital for developing successful strategies to curb diabetes and obesity.