Grant: Operating Grant

Two of the main challenges that multicellular organisms faced during evolution were to cope with invading microorganisms and eliminate and replace dying cells. The innate immune system evolved to handle both tasks. Key aspects of innate immunity are 1) the detection of invaders or tissue injury and 2) the induction of an inflammatory response. Both of these functions are governed by specific receptors of the innate immune system termed « pattern recognition receptors » (PRRs). In the gut, PRRs interact with commensal bacteria and induce a physiological level of inflammation, which is necessary for tissue integrity (homeostasis) and repair. While PRR activation in the intestine is essential for host resistance, it is detrimental when induced chronically or in excess and is linked to various diseases, notably inflammatory bowel diseases and cancer. Recent evidence from our laboratory has identified a tight crosstalk between innate immunity and proteins involved in apoptosis, or programmed cell death. The contribution of apoptosis to innate immunity is not restricted to the elimination of infected and damaged cells, as various effectors of the apoptosis machinery are emerging as critical for PRR signaling. We are investigating three classes of apoptosis effectors: 1) The Inflammatory caspases, 2) The inhibitors of apoptosis proteins (IAPs) and 3) The Bcl-2 family proteins. Our research program is aimed at understanding how these effectors contribute to the regulation of mucosal immunity in the intestine. Our ultimate goal is to find ways to manipulate their activity or modulate their downstream effects for therapeutic interventions. We will use experimental and genetic models of colitis, colorectal cancer and diarrheal disease, novel chemical compounds and genome-wide RNA interference to achieve our goals.