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Research | MCKINNEY LAB
Our laboratory is interested in the
pathogenesis of bacterial infections and we are using novel
techniques of bacterial gene regulation to dissect host-pathogen
interactions. The laboratory is investigating the effects of
dynamically modulating virulence gene expression in E. coli and
pathogenic Salmonella, using these bacteria as models of gram
negative pathogens responsible for a wide range of serious
infections. To modulate gene expression, the lab employs a system
of inducible gene product disruption, involving RNA molecules
called external guide sequences (EGSs) which target specific mRNA
for cleavage by cellular RNase P.
Past work using this system to down-regulate E. coli genes
essential to bacterial viability has shown the molecular and
cellular effects of EGSs exhibit reproducible time course
dynamics, dose-response, and synergy and are EGS oligonucleotide
sequence specific. Using a new Salmonella strain allowing for the
dynamic control of EGS expression triggered by various sugars,
recent work focuses on genes in the Salmonella SPI-1 pathogenicity
island, including the invB and invC genes involved in Salmonella's
invasion of host cells. The laboratory is seeking to dissect the
functions of, and dynamic interactions between, pathogenicity
genes in invasion and subsequent disease.
In ongoing work, the laboratory is taking advantage of the fact
that the RNase P enzyme is a ribozyme, in which RNA is
catalytically active. To this end, the lab is designing new RNA
molecules allowing for further analysis of the molecular
mechanisms of EGS effects in Salmonella, including new molecules
amenable to in vitro evolution and to studies of RNA biology in
bacteria.
Potential implications of these research efforts include gaining
insights to help develop new antimicrobial agents and strategies
designed to counter bacterial drug resistance, and to better
understand the various functions of RNA molecules in bacteria.
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SCHOOL OF MEDICINE
