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DTSTAMP:20130507T160000Z
UID:1367606799225@events.msu.edu
CATEGORIES:Conferences / Seminars / Lectures
DTSTART:20130507T160000Z
DTEND:20130507T170000Z
SUMMARY:Ashley Maiuri - Thesis Proposal Defense
DESCRIPTION:
 An In Vitro Approach to Classify Drugs According 
 to Their Potential to Cause Idiosyncratic 
 Hepatotoxicity In Humans\n
 \n
 HOST:  Robert Roth\n
  
  \n
 Drug-induced liver injury (DILI) is the 
 leading cause of acute liver failure in the 
 United States.  Idiosyncratic drug-induced liver 
 injury (IDILI), a subset of DILI, occurs 
 in a small fraction of patients taking a drug 
 and, although rare, can result in severe liver 
 injury or death.  Although the mechanisms 
 of IDILI are not well understood, it has been 
 hypothesized that an episode of inflammatory 
 stress can render an individual susceptible 
 to IDILI, and several animal models have been 
 developed based on this hypothesis.  These 
 models demonstrate that drugs associated with 
 IDILI increase and prolong lipopolysaccharide 
 (LPS)-stimulated tumor necrosis factor-alpha 
 (TNF) release.  The prolongation in TNF release 
 is critical to the pathogenesis of liver 
 injury.  Enhanced release of TNF is associated 
 with production of other inflammatory mediators 
 such as interferon-gamma (IFN) and with 
 activation of neutrophils that release toxic 
 factors such as elastase.  TNF, IFN, and elastase 
 contribute to hepatocellular damage in 
 IDILI models in vivo and in vitro.  The goal 
 of the proposed studies is to test the hypothesis 
 that the capacity of drugs to 1) increase 
 TNF production by macrophages in vitro and 
 2) sensitize hepatocytes to injurious effects 
 of inflammatory mediators (TNF, IFN, and elastase) 
 correlates with their potential to cause 
 IDILI in humans.  The data generated from 
 the proposed studies will be used to develop 
 a regression-based, supervised learning tool 
 to determine which combination of events (i.e. 
 a drug's ability to increase TNF release from 
 macrophages in vitro and/or a drug's ability 
 to sensitize hepatocytes to inflammatory mediators) 
 most accurately classifies the IDILI 
 potential of a drug.  Knowledge generated from 
 these studies will be useful in developing 
 an approach that could be used during preclinical 
 safety evaluation to identify drug candidates 
 with the potential to cause IDILI.\n
 \n\n
 Price: free\n
 Sponsor: Administration\n
 Sponsor's Homepage: http://phmtox.msu.edu/events/pdf/MAIURI%20A--Seminar%20Flyer%205-07-2013.pdf\n
 Contact name: Diane Hummel\n
 Contact phone: 884-3553\n
 Contact email: phm@msu.edu\n
 for more info visit the web at:\n 
 http://phmtox.msu.edu/events/pdf/MAIURI%20A--Seminar%20Flyer%205-07-2013.pdf\n
LOCATION:B448-449 Life Sciences
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