- Orsolya Kiraly
- Postdoctoral Associate
- Engelward laboratory
- Department of Biological Engineering
- Massachusetts Institute of Technology
- 77 Massachusetts Ave
- Lab: 617-750-7335 (Room 16-760)
- Cambridge, MA
- Email me through OpenWetWare
- 2008, Ph.D., Pathobiochemistry Semmelweis University, Budapest, Hungary
- 2002, B.S., Molecular Biology Eötvös Loránd University, Budapest, Hungary
I received my PhD for work on how rare mutations in pancreatic trypsin inhibitor contribute to chronic pancreatic inflammation. In the Engelward lab, my current work is aimed at homologous recombination in the pancreas in vivo.
While mitotic homologous recombination is an important DNA repair/tolerance mechanism, it can result in sequence rearrangements that can contribute to cancer. I am investigating the effects of DNA damaging chemicals, radiation, cell proliferation and DNA repair on homologous recombination in the pancreas.
The next question in my project is whether homologous recombination is induced by inflammation, which is a major risk factor for cancer.
In the lab of Miklos Sahin-Toth at Boston University, I was investigating the functional effects of mutations in SPINK1, the pancreatic secretory trypsin inhibitor. This inhibitor is an important line of defense against trypsin activity in the pancreas. It is important to inhibit any trypsin activity in the pancreas because trypsin activity can result in the activation of other digestive enzymes in a cascade reaction, which can lead to cell damage and pancreatic inflammation. We found that signal peptide mutations abolish the secretion of SPINK1 into pancreatic juice, and coding region mutations cause misfolding of the protein which is degraded intracellularly and is not secreted. In patients with these mutations, spontaneously activated trypsin is thus not inhibited by SPINK1, eventually resulting in autodigestion and inflammation.
At Semmelweis University I was studying the functional effects of polymorphisms in the promoter of the D4 dopamine receptor gene. This gene was the first one to be investigated in psychiatric genetics association studies, and its polymorphisms are associated with several personality traits. The functional effect of promoter polymorphisms was not known, however. With a reporter gene assay, we found that a duplication in the promoter decreases transcriptional efficiency, potentially influencing the number of receptor molecules and neurotransmission. However, the most widely studies SNP in the gene had no effect on gene expression in our assay. The apparent effect of this SNP in association studies is thus propably due to another variant which is in linkage disequilibrium with the candidate SNP.
My undergraduate thesis project at the Agricultural Biotechnology Research Center (in Gödöllő, Hungary) was aimed at generating host factor independent mutants of the 16-3 phage integrase by protein engineering. Integrases catalyze site-specific recombination which is harnessed in gene targeting. This project and the excellent mentoring I received at ABC gave me strong foundations in laboratory techniques in molecular biology and an interest in DNA metabolism and recombination.
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