The intestinal mucosa exists in a functional equilibrium with the complex lumenal milieu, which is dominated by a wide variety of commensal microbial species. Despite the continuous confrontation with bacterial products the normal mucosa exists in a state of minimal immune activation but must promptly mount an effective defense typically dependent on activation of inflammatory pathway when infection with a pathogen occurs. The overall goal of the present proposal is to define the mechanisms through which the epithelium interfaces with normal and pathogenic lumenal bacteria and the processes determining the functional outcome of those interactions whether normal homeostasis or active inflammation. These studies are based on the hypothesis that a recently identified family of pattern recognition receptor designated toll-like receptors (TLRs) found in preliminary studies to be present on the apical surface of intestinal epithelial cells allow the mucosa to sample the bacterial milieu and play a determining role in the functional outcome of that interaction. We also hypothesize that functional dysregulation of the TLR mediated responses eventuate in chronic intestinal inflammation. These preliminary studies have suggested that TLR4 which binds the ubiquitous bacterial cell wall product lipopolysaccharide (LPS) and TLR3 which binds other cell wall products may be especially pivotal as suggested by the finding of distinctive alterations in expression in human inflammatory bowel disease. These hypotheses will be evaluated through studies designed to address three specific aims: (I) To define the signaling pathways activated in intestinal epithelial cells by different TLRs following binding of cognate ligands, (II) To delineate the functional response of intestinal epithelial cells mediated through activation of TLRs, and (III) To determine the expression and functions of TLRs in inflammatory bowel disease in murine models and human IBD. These studies will encompass detailed assessment of the function of TLRs in model intestinal epithelial cells in vitro and both human tissues and novel murine models in vivo. Collectively these studies should provide new insights into the role of the TLRs, key elements of the innate immune system, in modulating the dynamic balance between controlled surveillance and appropriate response to mucosal challenge by lumenal flora.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060049-03
Application #
6711153
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$356,406
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Yassour, Moran; Vatanen, Tommi; Siljander, Heli et al. (2016) Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med 8:343ra81
de Luca, Antonella; Smeekens, Sanne P; Casagrande, Andrea et al. (2014) IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans. Proc Natl Acad Sci U S A 111:3526-31
Conway, Kara L; Kuballa, Petric; Khor, Bernard et al. (2013) ATG5 regulates plasma cell differentiation. Autophagy 9:528-37
Sokol, Harry; Conway, Kara L; Zhang, Mei et al. (2013) Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 145:591-601.e3
Conway, Kara L; Kuballa, Petric; Song, Joo-Hye et al. (2013) Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145:1347-57
Giallourakis, Cosmas C; Benita, Yair; Molinie, Benoit et al. (2013) Genome-wide analysis of immune system genes by expressed sequence Tag profiling. J Immunol 190:5578-87
Conway, Kara L; Goel, Gautam; Sokol, Harry et al. (2012) p40phox expression regulates neutrophil recruitment and function during the resolution phase of intestinal inflammation. J Immunol 189:3631-40
Wei, Shu-Chen; Rosenberg, Ian M; Cao, Zhifang et al. (2012) Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling. Inflamm Bowel Dis 18:877-88
Huett, Alan; Heath, Robert J; Begun, Jakob et al. (2012) The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe 12:778-90
Rivas, Manuel A; Beaudoin, Mélissa; Gardet, Agnes et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066-73

Showing the most recent 10 out of 33 publications