The aim of this project is to evaluate the role of the first Crohn's disease (CD) susceptibility gene, NOD2 in the development of chronic intestinal inflammation. There is increasing evidence that NOD2 is involved in the pathogenesis of CD from human CD susceptibility gene mapping studies and clinical genetic studies. Recent studies suggest that NOD2 expression is regulated by LPS and TNF, and NOD2 may sense bacterial LPS and activate NF-kB. Our lab has a mouse model (SAMP1/YitFc) of spontaneous chronic ileitis, which shares many features of human CD. This model provide us with a unique opportunity to investigate the abnormal expression of NOD2 in the development of chronic inflammation. To investigate NOD2 gene, first, the localization, distribution and half-life of NOD2 protein will be determined. Second, the magnitude and kinetics of NOD2 expression will be characterized at mRNA and protein levels in SAMP1/YitFc mice at different ages during the development of ileitis. Finally, the expression of Th1 cytokines and NF-kB associated genes will be explored in parallel with NOD2 expression. The overall objective of this project is to understand the function of NOD2 and associated inflammatory genes that may play a significant role in the development of Crohn's disease in order to prevent and treat this devastating disease more effectively.
