When aberrant, it contributes to human inflammatory disorders. Mutations in autophagy genes (ATG16L1 and IRGM) have been described as susceptibility factors of CD. Properly functioning autophagy prevents autoimmunity, assists in clearing pathogens, and plays a protective role during cell stress and injury. Normally the intruded bacteria-derived products are cleared from the intestinal wall by a process called autophagy. Autophagocytosis degrades aggregated proteins, removes damaged organelles, and eliminates intracellular microbes and bacteria-derived products. Inflammatory bowel disease (IBD) is a disorder characterized by chronic inflammation of the intestinal mucosa. The pathophysiology of IBD depends on both genetic susceptibility and environmental factors. Absorption and transport of solutes in the intestine are significantly perturbed during the course of IBD. Recently, we analyzed alterations in the intestinal expression levels of 15 solute carrier (SLC) transporters in healthy individuals and IBD patients. It has been demonstrated that pro-inflammatory cytokines, such as TNF and IFN-? induce the expression of human peptide transporter (hPEPT1), which transports muramyl dipeptide (MDP) a bacterial wall component of Gram-positive and Gram-negative bacteria. When present in the cytosol MDP activates Nod2, which can start the cascade of pro-inflammatory signaling. Background:
We postulate that the alteration in expression levels of SLC transporters in IBD patients is due to the effects of circulating pro-inflammatory cytokines and hypoxic conditions. Working Hypothesis:Our studies indicate that this may affect the absorption and transport of nutrients and biologically active compounds, including drugs, amino acids, and bacteria-derived products such as bacterial peptidoglycans (PGln), which in turn modulate autophagy and innate immune response.
The proposed study aims at the understanding of molecular mechanisms involved in the pathogenesis of IBD. Based on the current knowledge of the subject and both on our published and preliminary results we expect to gather essential information about the role of intestinal transporters in the pathology of IBD. :Proposed Project Expected Value of the
Keywords: solute carrier, intestinal transporters, inflammation, pro-inflammatory cytokines, autophagy, hypoxia, inflammatory bowel disease, bacteria-derived peptides, hypoxia