Many diseases of the human intestine are, in the active phase, histologically characterized by infiltration of the crypt epithelium by neutrophil (PMN). PMN subsequently accumulate in the crypt lumen to form """"""""crypt abscesses"""""""". The colonic lumen normally contains bacterial derived products such as N-formylated peptides in concentrations capable of activating PMN transmigration. Under my KO1 award I have demonstrated that i) fMLP (a model N-formyl peptide) is transported by the di-tripeptide/H + cotransporter hl?epT1; ii) hPepTl-r/iediated epithelial transport of fMLP enhances neutrophil-epithelial interactions; iii) hPepT1 can be aberrantly expressed in the colon under inflammatory states sueb as chronic ulcerative colitis and Crohn's disease; iv) hPepT1 mediated uptake of small n-formyl peptides, such as fMLP, into the cell cytoplasm increases immune accessory molecules such as MHC Class 1. In my first RO1 application [ propose to extend these finding at the molecular level. Thus the general aim of this proposal will be to better understand the intracellular signaling events (specific Aim#l) and the effect on the regulation of inflammatory responses (specific aim #2 and 3) of PepT1 mediated IMLP transport.
In specific aim#4, in vivo experiments will be aimed to study the inflammatory effects of hPepTl-mediated fMLP transport in the rat intestine and the in vivo functional effects of hPepT1 expression on the mice! colonic epithelial cells. The project involves a variety of biochemical methods with emphasis on_ molecular approaches. The completion of this proposal should molecularly define a link between anL active transport process and intestinal inflammation.
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