| The goals of the Ouellette lab are to define mechanisms of innate immunity in the mammalian intestinal epithelium, focusing on the biology of the Paneth cell in mice. In the small intestine, Paneth cells release high levels of a-defensins, termed cryptdins, into the lumen of the crypts of Lieberkühn, the site of life-long epithelial cell renewal. Secretion may be elicited by cholinergic stimulation or by exposure to bacterial antigens by Ca2+-mediated signalling processes. In mice, a defect in cryptdin precursor activation eliminates production of active cryptdins and impairs the ability to clear oral bacterial infections and increases susceptibility to Salmonella infection and systemic disease. Thus, these molecules function as endogenous antibiotics that influence the microenvironment of the crypt and resistance to bacterial colonization.
To understand this system in molecular terms, the lab investigates structure-activity relationships in cryptdins and their precursors, the molecular mechanisms that regulate a-defensin biosynthesis in Paneth cells, and Paneth cell differentiation during crypt ontogeny in fetal and newborn mice to define mechanisms that lead to the establishment of this component of mucosal immunity. |
