The intestinal epithelium represents the major interface between the mucosal immune system and the lumenal environment. The SAMP1/Yit mouse is a genetically inbred mouse line that develops ileitis that is similar to human Crohn's disease with near complete penetrance by 30 weeks of age. A major feature of disease in the SAMP/Yit mouse is the prominent architectural abnormalities of the ileal epithelium that occur early in the development of inflammation and ileitis. Ileitis does not develop in germ free SAMP/Yit suggesting a role for lumenal bacteria or environmentally-produced epithelial damage in the development of chronic iteal inflammation. These observations raise the hypothesis that SAMP1/Yit mice have an altered epithelial response to injury which results in abnormalities which, in turn, leads to chronic iteal inflammation.
Aim 1 will examine whether SAMP/Yit mice have an altered response to epithelial damage compared to control mice. The relationship of epithelial stem cell fate will be examined. Adoptive transfer techniques will be used to separate differences in injury-response that are intrinsic to the SAMP1/Yit epithelium from changes induced by the presence of activated T-cells and an inflammatory response. Changes in the expression of genes which regulate crypt epithelial apoptosis will also be examined.
In aim 2 we will determine whether the changes in epithelial architecture or differentiation present in the SAMP/Yit mouse induce alterations in epithelial production of molecules that regulate the inflammatory response. The production of epithelial derived cytokines will be examined in n epithelial cells isolated from mice with ileitis and from heritable alterations in the properties of the epithelial alterations in the properties of the epithelial cells or are induced by inflammation and ongoing epithelial damage.
In aim 3 we will examine heritable differences in epithelial expressed genes that may be involved in the development of ileitis in the SAMP/Yit mouse. This will be accomplished using cDNA microarray technology to identify differentially expressed genes that are encoded with chromosomal loci associated with susceptibility or development of disease as determined through the genetic analysis outlined in project 2.
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