Integrative Biology of the IL23R pathway


IL23 Receptor as a Confirmed Immune Disease Pathway


Chronic Inflammatory Diseases

The clinical focus of our research program is on chronic inflammatory diseases - Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus, psoriasis, type-1 diabetes, rheumatoid arthritis, multiple sclerosis etc. - that affect ~3-5% of the global population. Genome-wide association studies have revolutionized our ability to identify genetic risk factors for complex diseases, including inflammatory diseases. Several components of the IL-23 receptor (IL-23R) signalling pathway are validated disease risk factors. We will use unique genetic and biochemical methods and in vivo models to explore the role of this central pathway in CD and UC.  Despite our focus on CD and UC, given the extensive genetic overlap among inflammatory diseases, our discoveries will be relevant to other conditions studied by our large network of collaborators.

 

Objectives

The primary objective of our Team is to translate genetic discoveries into a better understanding of the biological processes influencing disease risk and advance the development of better diagnostic, prognostic and therapeutic options.

 

The Team

John D. Rioux, PhD | Associate Professor of Medicine, holder of the Canada Research Chair in Genetics and Genomic Medicine of Inflammation (Tier 2; 2005-) and researcher at the Montreal Heart Institute, a teaching hospital of the Université de Montréal. His work has been instrumental in the discovery not only of the haplotype structure of the human genome but also numerous genes for CD, UC, systemic lupus erythematosus and multiple sclerosis. He is the founding member of five international consortia studying the genetics of chronic immune mediated diseases. Most relevant to this project, is his work within the National Institute of Diabetes, Digestive and Kidney diseases IBD Genetics Consortium (NIDDK IBDGC) that led to the discovery that genetic variation within the IL23R, IL12ß, JAK2 and STAT3 genes are associated with CD and UC, as well as his important contributions to the International IBD Genetics Consortium (IIBDGC) of which he is Chair.

 

Sylvie Lesage, PhD | Assistant Professor of Microbiology and Immunology, is currently (2007-2011) a Chercheur Boursier (Junior 1) of the Fonds de la Recherche en Santé du Québec (FRSQ) and a researcher at the Hôpital Maisonneuve-Rosemont, a teaching hospital of the Université de Montréal. Dr. Lesage’s postdoctoral work within the Goodnow laboratory at the Australian National University led to a paradigm-shift in the field of autoimmunity and led to a series of high-impact publications. Specifically, her work demonstrated that organ specific autoimmunity is not only a result of failures in peripheral tolerance pathways but of failures of central tolerance pathways as well. These advances were a result of studies of a murine model of autoimmune diabetes (T1D) as well as extensive studies of how individuals carrying mutations in the AIRE gene develop a severe combination of organ specific autoimmune diseases, called APECED. Some of her more recent work has compared the immunological attributes of autoimmune-prone and -resistant mice and evaluated the biological impact of the cellular variations associated with autoimmune disease susceptibility.

 

Stephen Michnick, PhD | Professor of Biochemistry at the Université de Montréal, holder of the Canada Research Chair in Integrative Genomics (Tier 2; 2001-2010) and is a fellow of the Royal Society of Chemistry (UK). His group has developed experimental and conceptual frameworks to illuminate the dynamic organization of biochemical networks on a genome-wide scale. He developed universal strategies to study protein-protein interactions in live cells and to predict the drug action of small molecules (e.g., four potential anti-cancer agents) based on their perturbation of protein interactions. Dr. Michnick’s research also focuses on information processing in cell fate decisions. He has made contributions in chemical and structural biology, elucidating the molecular action of the immunosupressent drug FK506, recounted in the popular book “The Billion Dollar Molecule”, and a mechanism of cytokine-hormone receptor regulation.

 

Sylvain Chemtob, PhD, MD, FRCPC, FCAHS | Professor of Pediatrics, Ophthalmology, Optometry and Pharmacology, Canada Research Chair in Perinatology (Tier 2; 2001-), Canada Research Chair in Vision (Tier 1) and Léopoldine A. Wolfe Chair in Translation Research in Vision Sciences and a researcher at Hôpital Ste-Justine, a teaching hospital of the Université de Montréal. Dr. Chemtob’s laboratory has a proven track record in developing innovative noncompetitive allosteric modulators as potential therapies for inflammatory diseases. His group has the tools and experience to test peptides in highly relevant in vitro and in vivo assays and if required, convert peptides to small-molecule peptidomimetics for orally available compounds. Effective compounds have been developed for IGF-1RI and IL-1RI and  licensed to Allostera Pharma for formal preclinical development. Collectively, his research initiatives - academic and industrial - attest to Dr. Chemtob’s committed interest in receptor-targeted drug discovery. His group has already generated peptide antagonists specific to IL23R.

 

Press Releases

February 2010 | A research project at the Montreal Heart Institute is selected to receive a grant of more than $2.3 million from the Canadian Institutes of Health Research | Click to Read

October 2009 | Two major projects chosen by the Pfizer-FRSQ Innovation Fund are bringing together distinguished Quebec Researchers| Click to Read

 

Select Publications

Rivas MA et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011 Oct 9;43(11):1066-73 [PMID: 21983784]

Duerr RH et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006 Dec 1;314(5804):1461-3 [PMID: 17068223]

Sivanesan D et al. IL23R (Interleukin 23 Receptor) variants protective against inflammatory bowel diseases (IBD) display loss of function due to impaired protein stability and intracellular trafficking. J Biol Chem. 2016 Apr 15;291(16):8673-85 [PMID: 26887945]

Quiniou C et al. Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antagonist, decreases the inflammatory response.  Am J Physiol Regul Integr Comp Physiol. 2014 Nov 15;307(10):R1216-30 [PMID: 25354400]

Chognard G et al. The dichotomous pattern of IL-12r and IL-23R expression elucidates the role of IL-12 and IL-23 in inflammation. PLoS One. 2014 Feb 21;9(2):e89092 [PMID: 24586521]