November 20, 2009
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Intestinal disease genomics and how hedgehogs cause arthritis…
Genetic Clues to ‘Belly Aches’ in Children: The largest genomic investigation into early onset inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis involved the efforts of an international research team. In total, genetic information from 3,400 children with IBD and 12,000 healthy children were compared. This study resulted in the identification of five genetic regions associated with susceptibility to pediatric and adolescent IBD. The team is now taking a closer look at these regions to try to identify the specific proteins that may explain why or how the disease develops. Another question that they would like to address is why some individuals develop IBD early whereas others develop it later in life. Two Toronto researchers, Dr. Anne Griffiths (Sickkids) and Dr. Mark Silverberg (Mount Sinai Hospital), contributed their expertise to the study, which appears in this week’s issue of Nature Genetics.
Colon Cancer Susceptibility Genes: In another intestinal disease research project, scientists noticed that different strains of mice exhibited different levels of resistance or susceptibility to colon cancer induced by a chemical carcinogen. Using genetic studies, the determining factor was mapped to a specific region in chromosome 3 that they designated as colon cancer susceptibility locus 3 (Ccs3). Within this region are about 94 known genes and they have identified a subset that are expressed at high levels in the colon. What is also interesting is that Ccs3 in mice is homologous to regions in human chromosome 1 and 4, which also contain genes known to be associated with inflammatory bowel disease and colorectal cancer. This mouse model will be a very useful tool for future studies on the pathogenesis of colon cancer. Dr. Philippe Gros led the research team at McGill University and published the study in the journal Oncogene.
Hedgehogs are Key to Osteoarthritis: An unexpected discovery may hold the key to solving painful osteoarthritic disease. Elevated expression or activity of a group of proteins called Hedgehog resulted in the development of osteoarthritis in mice. In simple terms, the balance of this signalling pathway in chondrocyte cells determines whether they go on to make cartilage or bone. In the animal model of osteoarthritis, Hedgehog levels are high and there is less cartilage being produced from the chrondrocytes. Obviously, Hedgehog becomes an immediate pharmacologic target for the treatment or prevention of osteoarthritis. You may find it strange that this study on a disease primarily affecting adults is from The Hospital for Sick Children but it just shows that research is full of surprises and you never know where it may take you! Dr. Benjamin Alman and his research team reported their study in the online edition of Nature Medicine.
Pathway Signalling Antibody Production: A key signalling pathway required for the efficient production of antibodies was identified recently and verified using knockout mice. A receptor on T cells called ICOS (Inducible Costimulator) is required for their conversion into a specialized type of T cell called Tfh cells (follicular B helper T cells). As the name implies, their role is to help B cells make the right antibodies to the target. Dr. Woong-Kyung Suh’s team at Institut de recherches cliniques de Montréal discovered that ICOS activates an enzyme called phosphoinositide 3-kinase (PI3K), which eventually leads to the release of factors that trigger the formation of Tfh cells. With this knowledge, researchers may find ways to tweak the system to suppress (in autoimmune disease) or enhance (in infectious disease) antibody production as required. The study is reported in the Proceedings of the National Academy of Sciences.