The immune system of mucosal tissues must effectively protect the host from pathogen invasion, whilefacilitating homeostatic interactions with a diverse colonizing microbiota. A clear understanding of the keymolecules and mechanisms that achieve this delicate balance remains incomplete, leaving a gap in criticalknowledge. Paneth cells of the small intestine secrete large quantities of proteins and peptides into the lumenthat mediate both interrelated functions of host defense and maintenance of homeostasis. Compellingpublished evidence from many laboratories, including ours, suggests that defective Paneth cell functionincreases susceptibility to chronic inflammatory bowel disease (IBD) and to enteric pathogens. Thisinvestigation will focus on a secreted protein that our preliminary data suggests is among the most abundantsecretory proteins of human Paneth cells, an understudied intestinal lectin named intelectin. Intelectinorthologs widely span the animal Kingdom, from mammals to the invertebrate sea squirts. Recent publisheddata demonstrate that intelectin has molecular pattern binding activity characteristic of the innate immunesystem, in that it binds to carbohydrates found on a variety microbes - through interaction with exocyclic 1, 2diols - but does not bind to host carbohydrates because of steric hindrance. Our preliminary data identifyqualitative and quantitative aberrations of the two isoforms of intelectin (ITLN1 and ITLN2) in small intestinalspecimens from individuals with ileal Crohn's disease (CD) compared to controls. While statistically significant,the mechanisms that may tie these changes to impaired innate immunity in CD are unknown and will beinvestigated. Our hypothesis, based on published and preliminary data, is that intelectin is a critical mediatorof host-microbe interaction in the intestine. Aim 1 will determine the relative expression levels of ITLN1 andITLN2 in small intestinal CD and control specimens, and biochemically characterize intelectin isolated fromhuman small intestine. Aim 2 will investigate the in vitro activity of intelectin isoforms in vitro. Aim 3 willestablish innate immunological consequences of intelectin expression using newly generated C57BL/6 Itln-/-mice. Our goal is to elucidate a fundamental understanding on the role of intelectin in mucosal protection, andin so doing, fill a void in our understanding of a conserved, highly abundant secretory protein of human Panethcells. Successful completion of these studies will likely have broad impact on our mechanistic understandingof innate immunity in the small intestine.
|Effective start/end date||6/15/16 → 5/31/21|
- National Institutes of Health: $467,075.00