This proposal describes a 5-year training program for the development of an academic career in surgery. The principal investigator (PI) is an Assistant Professor with joint appointments in the Divisions of Pediatric Surgery at the University of Maryland and Johns Hopkins University. The overall objective is for the PI to expand his scientific arsenal with the long-term goal of becoming an independent scientific investigator. James Nataro M.D., Ph.D. will be his primary mentor; he is an expert on the pathogenesis, genomics, molecular epidemiology and diagnosis of enteroaggregative E. coli. He has trained numerous postdoctoral fellows and graduate students. The University of Maryland at Baltimore, which includes its Center for Vaccine Development and the Mucosal Biology Research Center, offers a superb environment for basic science research as well as multidisciplinary collaborations. A description of the research project follows: Defined as little or no bile flow, cholestasis is a common condition associated with significant and sometimes devastating complications in both children and adults. Cholestasis is known to be associated with the failure of intestinal barrier function; bacteria and other substances from the intestine enter the circulation and initiate a systemic inflammatory response which causes impairment of multiple organs. If cholestasis progresses unchecked, liver or multivisceral transplantation may be necessary for survival. Less fortunate patients may not survive to transplantation. It remains unclear why some patients are predisposed to more significant complications than others. We have observed differences in the systemic inflammatory responses and outcome following common bile duct ligation (CBDL) between two inbred mouse strains, C57BL6/cJ (B6) and A/J, suggesting a genetic contribution. The B6 mice become more ill and die sooner than the AJ mice. We hypothesize that the genetic background dictates the degree of intestinal inflammation and permeability, systemic inflammatory response and resultant morbidity and mortality following extrahepatic biliary obstruction. First, we will measure intestinal permeability and perform bacterial translocation studies on the two strains following CBDL. Second, we will determine what role the TLR2 and TLR4 signaling pathways play. Third, we will determine what role the NOD1 and NOD2 signaling pathways play. The mechanism and genes behind the differences noted in this mouse model are likely to participate in the same fashion in humans and may ultimately provide a basis for identifying individuals at risk for more frequent and more severe sepsis followina cholestasis. [unreadable] [unreadable] [unreadable]