Project description
Insight into goblet cell biology
The mucus layer that coats the interior surface of the gastrointestinal tract serves as the first line of defence against microorganisms and their by-products. It also allows gut microbiota to thrive and maintain gut health. Epithelial goblet cells, a type of specialized cell, secrete glycoproteins that make-up the mucus layer and are considered to play a key role in gut health and disease. The EU-funded GCMech project aims to study how goblet cells respond to changes in conditions at the translational level and why they dysfunction during inflammatory bowel diseases. Researchers will focus on the role of inflammation, autophagy and antibiotics offering fundamental insight into goblet cell biology, opening new opportunities for the treatment of gut-related disorders.
Objective
Goblet cells are specialized epithelial cells that secrete mucus and antimicrobial proteins which together form the gut mucus barrier. The mucus barrier protects the host from bacterial invasion and subsequent activation of an inflammatory response, while also providing food for the microbiome. Dysfunction of goblet cells and high penetrability of the mucus barrier are hallmarks of inflammatory bowel diseases (IBD). While the reasons for goblet cell dysfunction are unclear, it is thought that inflammation, host genetics (specifically mutations in autophagy genes) and environmental factors can affect their function. Yet despite their importance, the basic biology of goblet cells is not understood as they are part of a heterogeneous tissue. I developed a new mouse model that allows isolation of ribosomes specifically from goblet cells in vivo, thus revealing the translational response of goblet cells to various conditions. In preliminary studies we found that altering the autophagy process in vivo led to modification of the colonic mucus barrier, alteration of the microbiome and resistance to colitis. We also found that antibiotic treatment, an environmental factor which increases the risk for IBD, altered the mucus barrier and instigates gut inflammation in mice. Our goal is to mechanistically determine how inflammation, autophagy and antibiotics affect goblet cell function during health and IBD. We will 1) define goblet cell function during IBD development in vivo and test if goblet cells fail to regain proper function during remission, leading to relapse. We will also 2) use a novel mouse model of augmented autophagy to determine the role of autophagy in preserving goblet cell function during IBD. Lastly, 3) we will use germ-free mice to reveal the microbiome-dependent and -independent effects of antibiotics on goblet cell function and IBD. Our study will provide new understanding of goblet cell biology and may lead to new therapeutics which target goblet cells.
Fields of science
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- natural sciencesbiological sciencesmicrobiology
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
52900 Ramat Gan
Israel