Sepsis and the development of multi-system organ failure remain major causes of death in patients with underlying liver disease, particularly following surgical intervention. Though several studies have pointed to an altered immune response to infectious stimuli in the setting of liver disease, the exact nature of this response is yet to be defined. There are numerous reports of a hyper-inflammatory response following infection in both humans and rodents with biliary obstruction, however there is also evidence of an increase in anti-inflammatory cytokines in these same patients and animals. Therefore, the purpose of these studies will be to define the exact nature of the inflammatory response to Gramnegative infection in animals with biliary obstruction using a validated microarray immunoassay, and to determine if modulation of the inflammatory response will lead to decreased organ injury and death. Ultimately, the results of these studies will provide insight into the immune response to infectious stimuli in the setting of cholestatic liver disease. Until this response is well understood, it will be difficult to develop effective strategies for the treatment and prevention of septic complications in these patients. Hypothesis: The increased mortality observed in the setting of biliary obstruction and Gram-negative infection is mediated by a dynamic fluctuation between a pro- and anti-inflammatory state.
Specific Aim I : Define the inflammatory response present in the setting of biliary obstruction with and without concomitant Gram-negative infection.
Specific Aim II : Modify a previously validated microarray immunoassay technology to simultaneously determine the level of constitutive and acute phase proteins, bacterial content, and degree of liver injury in murine samples.
Specific Aim III : Determine if lethality following Gram-negative bacterial infection in animals with biliary obstruction can be improved with strategic modulation of the inflammatory response. This grant proposal encompasses a training program for the principal investigator including coursework and frequent didactic sessions with mentors and advisors. yVith the guidance of the candidate's advisory committee and the institutional support provided by the University of Michigan's Department of Surgery, the candidate will develop the skills necessary to evolve into a successful independent investigator.
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|Xiang, Zuoshuang; Minter, Rebecca M; Bi, Xiaoming et al. (2007) miniTUBA: medical inference by network integration of temporal data using Bayesian analysis. Bioinformatics 23:2423-32|