Eric Ogier-Denis, PhD: is Research Director at the National Institute of Health (INSERM) and is the Head of the research team entitled: "Cellular Stress and Inflammatory Bowel Diseases". After his PhD Thesis (1989) he was nominated Research Manager (1990) and Director of Research (2002) at the INSERM. Since 2002, he focuses his research on inflammatory diseases and has obtained grant from Hospital to manage clinical research on inflammatory bowel diseases (Interface Fellowship AP-HP). He will supervise the scientific study as expert in the field of intestinal differentiation and inflammatory bowel diseases. Throughout his career, he received strong competitive support from international granting agencies for his participation in the design and coordination of fundamental projects in the field of gastroenterology.
The Research Team into the Centre of Research CRB3 INSERMU773 belongs to the recently labelised LabEx (Laboratory of Excellence on Inflammation:INFLAMEX) is devoted to Inflammatory Bowel Diseases (IBD) and provides the scientific expertise, human resources and technical facilities to run this project. Our team gathers the skills of i)-senior basic research scientists that set up new methodological approaches to address the importance of yet unexplored regulatory mechanisms that may contribute to the intestinal differentiation and inflammation, ii)-clinicians (Department of Gastroenterology, Beaujon Hospital) specialised in chronic IBD and Short Bowel Syndrome, and iii)- pathologist specialized in gastroenterology. Our team has expertise on, IBD (members of the team are involved in the IBD research association REMIND and in the GETAID network which coordinates national clinical trials for IBD), and basic expertise in ER stress, oxidative stress, microRNAs, intestinal inflammation, intestinal differentiation, innate immunity, and colorectal cancer. The research has been supported by several grants focusing on chronic inflammatory bowel diseases, including PNRHGE (Progamme National de Recherche en Hépato-Gastroentérologie) 2007-2008, the IBD patients association François Aupetit 2006-2007-2008-2010 (AFA) and industrial contracts.
The general goal of the team's project is to better understand the disease mechanisms underlying the development of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC). The main interest is to uncover the pathophysiological mechanisms of IBD, in particular of UC. The works are based on genetic and biochemical studies performed on large cohorts of patients, original animal models of experimental colitis, inflammatory signalling pathway analyses, and molecular analyses of human tissue samples.
Clinical data and known risk factors suggest that congenital or acquired disorders, restricted to colonic epithelium, may have an initial role in the induction of inflammation in UC. In this context, it is suggested that initiation of inflammation may be linked to an inability to manage the Unfolded Protein Response (UPR) within the epithelial barrier. UPR is involved in the resolution of endoplasmic reticulum (ER) stress allowing cell adaptation and responsiveness to environmental changes. Indeed, genetic variations of the transcription factor X-box Protein 1 (XBP-1), a key actor of UPR, have been associated with IBD because intestinal invalidation of this gene induces spontaneous enteritis and sensibility to colitis by loss of secretory cells (Paneth and mucosecretory cells) in mice. Furthermore, impairment of proper ER stress resolution has been identified in epithelial cells from canonical murine models of colitis as a primarily originator of intestinal inflammation. These recent results suggest a major role of ER stress in the pathophysiology of experimental colitis.However, involvement of ER stress in the pathophysiology of human UC remains to be demonstrated.
Our research project is developed to address an analysis of ER stress in UC from its genetic regulation to its environmental modulation using relevant in vitro and in vivo experimental models and essential human samples. Research on cell abnormalities that may alter epithelial barrier homeostasis facing environmental changes is essential to understand the pathophysiology of UC. In agreement with the fact that early decrease in mucosecretion is a histological pattern of UC, several recent experimental data suggest that goblet cells are particularly sensitive to deregulation of the ER stress. Thus, inability to manage ER stress may not only be a primary originator of intestinal inflammation but also a perpetuator of inflammation when ER stress is modulated secondarily to inflammatory mediators or microbial factors. Our data pointed out to unresolved ER stress in colonic mucosa from UC patients without obvious histological inflammation suggesting that primitive ER stress deregulation impairs the capacity of colonic epithelium, and more particularly goblet cells, to cope with stress modulators derived from the local environment (bacteria, food digestion products, polluants…). In line, deregulation of ER stress may result in the activation of inflammatory signals relayed and perpetuated by immune cells.