Grant: CIHR Fellowship

Affecting more than 10 million people worldwide, Inflammatory Bowel Disease (IBD) is characterized by severe chronic inflammation in the gastrointestinal tract. It disrupts an individual's ability to digest food and eliminate waste thus subjecting them to increased risk of developing comorbidities. More than 200 genetic risk loci determine susceptibility to developing IBD. Beyond the dichotomy between its major forms, Crohn's disease and colitis, sub-phenotypes exist, making care of IBD patients challenging. To date, IBD is incurable, and there is no one-size-fits-all treatment approach. This necessitates the discovery of prognostically informative biomarkers that can drive personalized selection of therapy in IBD patients. Due to altered metabolism and local ischemia, protons are produced in excess rendering the inflamed intestinal microenvironment acidic. Immune cells sense the extracellular acidity and modulate their inflammatory response to maintain tissue homeostasis. A class of proton-sensing G protein-coupled receptors have emerged as functional pH sensors, capable of altering immune cell inflammatory programs in response to acidic pH. Our group has uncovered a novel role for GPR65, a risk gene associated with IBD, in modulating inflammatory properties of immune cells and conferring protection against infection and inflammation in response to acidosis. Our preliminary work suggests that loss of GPR65 signaling leads to increased metabolic acidosis and mortality in response to systemic inflammation. GPR65 deficiency enhances immune activation and antimicrobial responses to colitis. My project aims at identifying the molecular pathways and cellular functions affected by the loss of GPR65 and delineating the significance of pH sensing in chronic inflammation. Hence, this study will highlight the significance of pH sensing in intestinal homeostasis and may serve as a blueprint for developing IBD therapeutic targets in the remediation of intestinal inflammation.