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>> *To:  The George Mason University Community*
>>
>> *Anne B. Verhoeven
>> PhD Biosciences Candidate
>> *
>> *Date:   Thursday June 17, 2010
>> Time:   10:30 a.m. 
>> Place:  George Mason University
>> ** 	     Room 256, Bull Run Hall
>> 	     Prince William campus <http://www.gmu.edu/resources/visitors/findex.html>
>>   
>> Dissertation Chair: Dr. Monique van Hoek
>> Committee members: Dr. Emanuel Petricoin III, Dr. Yuntao Wu, Dr. Timothy Born*
>>
>> *Title: "An Analysis of Early Signaling Pathways Activated by /Francisella Tularensis/ Infection"*
>>
>> A copy of the dissertation is on reserve in the Johnson Center 
>> Library, Fairfax campus.  The doctoral project will not be read at 
>> the meeting, but should be read in advance.
>>
>> All members of the George Mason University community are invited to 
>> attend.*
>> *
>>
>> *ABSTRACT:
>> *
>> /Francisella tularensis /is a zoonotic, gram negative pathogen that 
>> in recent years has become a pathogen of increasing interest because 
>> of its bioterrorism implications.  /Francisella /has been classified 
>> as a Type A pathogen by the CDC.  It is capable of producing severe 
>> infection with doses as low as 10 organisms.  The possible threat of 
>> /Francisella /as a biological weapon makes understanding its specific 
>> pathogenicity of utmost importance. 
>> /Francisella /is an intracellular pathogen that enters the cell 
>> through an unknown method.  Infection from /Francisella /occurs in 
>> many different cell types, including macrophages, hepatocytes, and 
>> endothelial cells.  Once in the cell, /Francisella /is encapsulated 
>> in a phagosome.  Between 2-4 hours after the initial infection 
>> /Francisella /escapes the phagosome and proceeds to replicate in the 
>> hosts cytosol.  Previous studies have demonstrated that /Francisella 
>> /inhibits the release of pro-inflammatory cytokines such as 
>> TNF-alpha, IL-1, IL-12, and IL-8, thus hampering the ability of the 
>> innate immune system to respond to infection.  Also, there is an 
>> increase of IL-10 seen during /Francisella /infection.  IL-10 is an 
>> anti-inflammatory cytokine that further decreases the innate immune 
>> system response.  The lack of proper cytokine production might be 
>> caused by /Francisella/'s ability to block the TLR pathways, CR3 
>> pathways, and the apoptosis pathways, further impeding the innate 
>> immune response.  Interestingly, /Francisella /does not employ any 
>> known secretion systems, such as type III or type IV secretion 
>> systems that are commonly found in pathogenic bacteria.  Nor does it 
>> produce toxins that could explain its ability to block cell signaling 
>> pathways.  The mechanism used by /Francisella /to directly interact 
>> with host cell pathways is still unknown.
>> *We hypothesize that by looking at specific pathways that are 
>> activated during infection of J774A.1 macrophages by /Francisella 
>> tularensis /LVS and /Francisella novicida, /we will be able to obtain 
>> a phosphorylation map of activated host cell responses which could 
>> lead to novel therapeutics.* The steps that we will use to accomplish 
>> this task are: 1) the use of Reverse Phase Protein Microarray 
>> analysis to generate a phosphorylation map of /Francisella /LVS and 
>> /Francisella novicida/ infection in J774A.1 cells, 2) validation of 
>> this map through western blots and analysis of previous reported data 
>> on specific signaling pathways, 3) comparison of different 
>> phosphorylation maps of /Francisella novicida /and /Francisella /LVS 
>> to determine differences between the strains, and 4) in a separate 
>> study, we will examing changes in gene expression in human lung 
>> epithelial cells through the use of microarrays to determine the 
>> difference in host cell gene transcription between uninfected A549 
>> cells and /Francisella /LVS infected A549 cells.
>>
>>
>> ###