Scientific Presentations Summer 2009 - Dana-Farber/Harvard ...

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Identification of novel genes that influence virulence of vibrio cholerae Cindy Capitolin Mentor: Paula Watnick, MD, PhD Scientific Advisor: Alexandra Purdy, PhD Children’s Hospital Boston Cholera, a fatal disease characterized by severe diarrhea, is caused by a Gram-negative bacterium called Vibrio cholerae which is acquired via ingestion of contaminated food or water. Although cholera is practically non-existent in the US, it is a major concern in the developing world, particularly in countries with poor sanitation. Identification of the genes required for intestinal survival of the Vibrio cholerae bacterium will help us to understand the pathogenesis of this disease and develop new ways of treating cholera. The toxin-co regulated pilus and cholera toxin, which are responsible for the intense diarrhea that is seen in cholera, are already known to be essential for virulence of V. cholerae. We hypothesize that there are additional genes that contribute to the virulence of Vibrio cholerae. The purpose of this study is to identify these genes. The Watnick lab has developed Drosophila melanogaster as a model organism for the study of cholera. Several virulence-defective mutants were identified in a primary screen. In my study, survival assays were set up in Drosophila and the virulence defect of 8 transposon insertion mutants was confirmed. Colonization assays were then set up in order to determine the ability of each specific mutant strain to survive in and colonize the Drosophila intestine. We also isolated, amplified and sequenced the transposon insertion sites of each of these mutant strains. Thus far we have identified the transposon insertion sites of four mutant strains. These include flagellar synthesis genes, a phosphate transport system, and an uncharacterized ABC transport system. We anticipate that at the end of this project we will discover and characterize other genes that are relevant to the virulence of Vibrio cholerae.
Determination of Elafin’s role in cellular proliferation in the ovarian cancer microenvironment Amber Channer Mentor: Ronny Drapkin, MD, PhD Scientific Advisor: Adam Clauss, PhD Dana-Farber Cancer Institute Ovarian cancer is a major cause of cancer-related mortality in women worldwide. Unfortunately, the lack of efficient screening methods results in the majority of patients being diagnosed with late stage ovarian cancer, when a surgical cure is highly unlikely. Although most patients with advanced stage disease initially respond to chemotherapy, the majority ultimately relapse with chemo-resistant tumors. Therefore, there is a pressing need to develop serum biomarkers for early detection. We have previously described two potential biomarkers: HE4 and Elafin. Both are located in the WAP locus on chromosome 20q13, a region frequently amplified in ovarian cancers. The FDA recently approved the HE4 ELISA test, in conjunction with CA125, to monitor patients with ovarian cancer for recurrence. Elafin is a secreted serine protease inhibitor, which has shown to specifically inhibit Elastase, a serine protease. We know that the protease function of Elastase is important to release TGF-ß and thereby active it. TGF-ß (Transforming Growth Factor) is a secreted protein that mainly functions to inhibit epithelial proliferation, tumor development and morphogenesis. During oncogenesis, TGF-ß is silenced and cannot control the cell cycle, thus enabling cells to grow uncontrollably. This work aims to characterize the role Elafin plays in the ovarian cancer microenvironment. We hypothesize that by inhibiting Elastase, Elafin prevents the release of active TGF-ß. To analyze we will transform a panel of ovarian cell-lines with either wild type Elafin, which has been previously shown to increase cellular proliferation, or two mutated forms of Elafin (M25K and M25G). The mutation of methionine to a lysine or a glycine generates a protein that no longer functions as a serine protease inhibitor. By comparing the proliferation effect of the wild type Elafin versus the mutated counterpart, we will be able to tell whether the serine protease inhibitor function of Elafin is necessary for its role in increasing cellular proliferation.
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