The current proposal is aimed at providing the candidate with an in-depth training in the area of host- microbial interactions along with formal courses at the graduate level to enhance his research and laboratory skills. The expertise of the sponsor and co-sponsor combined with a highly interactive basic- research environment in the Department of Medicine at the University of Illinois at Chicago, offer a great training opportunity for the applicant to achieve his long-term goals of becoming an independent research investigator in gastrointestinal physiology with special emphasis on basic research. The proposed studies are focused at examining the role of intestinal apical sodium-dependent bile acid transporter (ASBT) in the pathophysiology of diarrhea associated with infection by an important food-borne pathogen, Enteropathogenic E. coli (EPEC). To date, the mechanism(s) underlying EPEC-associated early diarrhea are not clear. In this regard, ASBT which is responsible for the absorption of the majority of bile acids from the intestinal lumen, has been implicated in diarrhea associated with inflammatory diseases. Disturbances in ASBT function have been associated with increased luminal bile concentration in the small intestine and colon, which in turn can influence electrolyte absorption and secretion, causing diarrhea. Therefore, we hypothesized that EPEC-induced diarrhea might involve a decrease in intestinal bile acid transport processes. Our preliminary data showed a decrease in ASBT function in response to EPEC infection in human intestinal Caco-2 cell monolayers. The present studies will explore the effects of EPEC infection on ASBT activity and expression both in in vitro and in vivo models and elucidate the signal transduction and underlying membrane trafficking events. Studies in Specific Aim 1 will determine the effects of EPEC on ASBT activity in model human small intestinal (Caco-2 monolayers) along with investigating the role of EPEC virulence genes and kinetic parameters of EPEC mediated effects on ASBT activity.
Specific Aim 2 will elucidate the role of EPEC induced signal transduction pathways and membrane trafficking events involved in modulation of ASBT function and expression.
Specific Aim 3 will critically examine the effects of EPEC and its mutants on bile acid transport in the ileum utilizing the in vivo murine model of EPEC infection. The results from these studies will not only increase our understanding of the mechanisms of regulation of human intestinal bile acid transporters and their modulation by pathogenic organisms but will also provide a basis for the pathogenesis of EPEC-induced diarrhea which might aid in the development of improved therapeutic modalities in future. ? ? ?
| Annaba, Fadi; Ma, Ke; Kumar, Pradeep et al. (2010) Ileal apical Na+-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin. Am J Physiol Gastrointest Liver Physiol 299:G898-906 |
| Annaba, Fadi; Kumar, Pradeep; Dudeja, Amish K et al. (2010) Green tea catechin EGCG inhibits ileal apical sodium bile acid transporter ASBT. Am J Physiol Gastrointest Liver Physiol 298:G467-73 |
| Sarwar, Zaheer; Annaba, Fadi; Dwivedi, Alka et al. (2009) Modulation of ileal apical Na+-dependent bile acid transporter ASBT by protein kinase C. Am J Physiol Gastrointest Liver Physiol 297:G532-8 |
