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Robert
Blumenthal,
PhD.,
Professor
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Gene
Regulation and Evolution
in
Bacteria
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Faculty:
Robert Blumenthal, PhD.
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Summary: The
Blumenthal lab focuses on two areas critical
to understanding the development of bacterial
pathogenicity and antibiotic resistance
- the mechanics and logic of gene regulation
in bacteria, and the flow of genes between
bacteria. These problems are related
to one another: conserved regulatory
mechanisms can improve a gene's mobility
if the gene is properly regulated in
new host cells, while the extent of gene
flow between bacteria depends on the
relative levels of expression of restriction
endonucleases, modification methyltransferases,
and recombination enzymes in the recipient
cells. Many of these questions are designed
to refine bioinformatic analyses of microbial
genome sequences by testing some of the
underlying assumptions.
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Dr.
Blumenthal grew up in microbiology labs - his father,
Dr. Harold J. Blumenthal (1926-2003), studied the
metabolism of Gram-positive bacteria and was chair
of the microbiology department at Loyola University
(Chicago) for many years. The younger Dr. Blumenthal
majored in microbiology at Indiana University (A.B.
1972), and earned his M.S. (1975) and Ph.D. (1977)
in microbiology at the University of Michigan in
the lab of Dr. Fred Neidhardt. His thesis focused
on a proteomic analysis of transcription termination
factor effects in the bacterium Escherichia coli.
This was followed by postdoctoral work with Dr.
Pat Dennis at the University of British Columbia
(regulation of RNA polymerase synthesis), Dr. Lorne
Babiuk at the University of Saskatchewan (gene
regulation in rotavirus), and Nobel laureate Dr.
Rich Roberts at the Cold Spring Harbor Laboratory
(adenoviral RNA splicing, regulation of restriction-modification
systems, bioinformatics). He has also spent two
sabbatical leaves at the University of Michigan
with Dr. Rowena Matthews (catalysis of methyltransfer,
DNA-protein interactions).
Architecture
of the Lrp regulon in various bacteria.
The Leucine-responsive
Regulatory Protein (Lrp) directly controls over
70 genes and operons in Escherichia coli (and indirectly
controls several hundred more), and among the directly-controlled
genes are many associated with virulence. Lrp is
highly conserved among bacteria ranging from E.
coli and Salmonella typhi through Vibrio cholerae
and even, to a lesser extent, Haemophilus influenzae.
Do the regulatory networks (regulons) controlled
by Lrp have the same basic structure in all of
these different bacteria? If not, how has the regulon
structure changed? What are the implications of
any changes found on bioinformatic predictions
of gene regulation from genome sequences? These
studies are funded by an NIH grant to Dr. Blumenthal,
with subcontracts to laboratories at Minnesota
(Enterohemorrhagic E. coli (EHEC) and statistical
analysis of microarray data; http://www.cbs.umn.edu/BMBB/faculty/Khodursky.A.B.shtml),
Stanford (Vibrio cholerae; http://schoolniklab.stanford.edu/),
and Michigan (Proteus mirabilis; http://www.med.umich.edu/microbio/bio/mobley.htm).
 Control
of restriction-modification systems by an unusual
transcriptional activator.
In our studies of the
PvuII restriction-modification system, isolated from
the Gram-negative urinary tract pathogen Proteus
vulgaris, we discovered that the restriction endonuclease
gene is controlled by an activator. This activator
is found in a variety of other restriction-modification
systems, including some from Gram-positive organisms
such as Bacillus; surprisingly, the activators from
Proteus and Bacillus work in both genera. Even more
surprising is the fact that these activators have
only about 9.5 kDa subunit masses. How does this
new type of activator work? How is the essential
temporal control of this system linked to the regulatory
logic (the activator controls its own gene, and is
also a repressor at higher concentrations)? These
studies are funded by an NSF grant to Dr. Blumenthal,
and a new collaboration is beginning with a laboratory
at Cal-Davis to study the regulatory circuit design
principles (http://www.bme.ucdavis.edu/profiles/savageau.html).
Basis
for hypervirulence of the USA300 lineage of community-acquired
methicillin-resistant Staphylococcus aureus (CAMRSA).
These studies began when a colleague (http://utmc.utoledo.edu/physicianapp/physingle.jsp?ID=483),
an infectious diseases specialist in the Department
of Pediatrics at UT, became concerned about the
rapidly-growing number of serious skin and soft
tissue infections due to CAMRSA in her patient
population. These studies use comparative genome
hybridization on microarrays to analyze patient
isolates, and focus on the roles of specific genes
in colonization and pathogenesis.
Current
Grant Funding:
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NIH
(NIAID) - Conservation and Adaptation
of a Regulon Across Genera
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NSF (MCB) - Genetic Switch Controlled by
an Unusual Family of Transcription Activators
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