Rao:Projects

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Revision as of 21:35, 16 December 2010

Rao Lab

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Salmonella Pathogenesis

Salmonella is the causative agent for a wide range of diseases in humans, including gastroenteritis and enteric fever. Worldwide, Salmonella is estimated to cause over sixteen million cases of typhoid fever, resulting in approximately six hundred thousand deaths, and over one billion cases of acute gastroenteritis, resulting in approximately three million deaths, each year. Over five hundred genes in Salmonella are directly involved in pathogenesis. Yet, only a subset of these is expressed at a given time. Currently, an integrated model for differential gene expression is lacking. To address this problem, we are investigating how Salmonella dynamically regulates gene expression during the different phases of the infection cycle. By characterizing how these genes are coordinately expressed and regulated, we aim to understand the infection process and, more importantly, discover novel targets for antibiotics.

Role of cross talk in regulating the dynamic expression of the flagellar Salmonella pathogenicity island 1 and type 1 fimbrial genes
Journal of Bacteriology, 192(21):5767-77, 2010
Saini S, Slauch JM, Aldridge PD, Rao CV
PubMed PDF

The role of coupled positive feedback in the expression of the SPI1 type three secretion system in Salmonella
PLoS Pathogens, 6(7):e1001025, 2010
Saini S, Ellermeier JR, Slauch JM, Rao CV
PubMed PDF

SprB is the molecular link between Salmonella pathogenicity island 1 (SPI1) and SPI4
Journal of Bacteriology, 192(9):2459-62, 2010
Saini S, Rao CV
PubMed PDF

The Salmonella SPI1 type three secretion system responds to periplasmic disulfide bond status via the flagellar apparatus and the RcsCDB system
Journal of Bacteriology, 190(1):87-97, 2008
Lin D, Rao CV, Slauch JM
PubMed PDF

Designing orthogonal factors for regulating transcription and translation

The goal of synthetic biology is to engineer and reprogram cellular processes for producing novel compounds and also improving health and the environment through the rational implementation of well-characterized genetic components. Introducing novel functionality into cells, however, requires components that do not interfere with native cellular processes. As we consider more complex synthetic biology applications, greater premium will be placed on expanding our genetic toolbox. Towards this goal, our lab has developed a set of computational algorithms for reprogramming the specificity of transcriptional factors and ribosomes in bacteria. In both cases, we were able to experimentally validate these algorithms.

A central theme in both applications is the engineering of orthogonal pairs of regulatory factors, orthogonal in the sense that the engineered factor binds a sequence not recognized by the native factor but does not bind the sequences that are recognized by the native factor.

Engineering transcription factors with novel DNA-binding specificity using comparative genomics
Nucleic Acids Research, 37(8):2493-503, 2009
Desai TA, Rodionov DA, Gelfand MS, Alm EJ, Rao CV
PubMed PDF

Computational design of orthogonal ribosomes
Nucleic Acids Research, 36(12):4038-46, 2008
Chubiz LM, Rao CV
PubMed PDF

Bacillus subtilis Chemotaxis

We are investigating chemotaxis in the model Gram-positive bacterium Bacillus subtilis. While Escherichia coli has long been the paradigm for bacterial chemotaxis, the pathway architecture is not conserved in other species of bacteria. Interestingly, B. subtilis behaves in an identical manner to E. coli with regards to chemotaxis. The pathways in the two bacteria also have homologous proteins. Yet, how these proteins are “wired” to one another in the two pathways is entirely different. We seek to understand why these two pathways are “wired” differently and the extent of degeneracy in the basic design.

Attractant binding induces distinct structural changes to the polar and lateral signaling clusters in Bacillus subtilis chemotaxis.
Journal of Biological Chemistry, November 2010,
Wu K, Walukiewicz HE, Glekas GD, Ordal GW, Rao CV
PubMed

Site-specific methylation in Bacillus subtilis chemotaxis: The effect of covalent modifications to the chemotaxis receptor McpB.
Microbiology, September 2010,
Glekas GD, Cates JR, Cohen TM, Rao CV, Ordal GW
PubMed

A PAS domain binds asparagine in the chemotaxis receptor McpB in Bacillus subtilis
Journal of Biological Chemistry, 285(3):1870-8, 2010
Glekas GD, Foster RM, Cates JR, Estrella JA, Wawrzyniak MJ, Rao CV, Ordal GW
PubMed PDF

The molecular basis of excitation and adaptation during chemotactic sensory transduction in bacteria
Contributions to Microbiology, 16:33-64, 2009
Rao CV, Ordal GW
PubMed PDF

The three adaptation systems of Bacillus subtilis chemotaxis
Trends in Microbiology, 16(10):480-7, 2008
Rao CV, Glekas GD, Ordal GW
PubMed PDF

Phosphatase localization in bacterial chemotaxis: divergent mechanisms, convergent principles
Physical Biology, 14;2(3):148-58, 2005
Rao CV, Kirby JR, Arkin AP
PubMed PDF

Design and diversity in bacterial chemotaxis: a comparative study in Escherichia coli and Bacillus subtilis
PLoS Biology, 2(2):E49, 2004
Rao CV, Kirby JR, Arkin AP
PubMed PDF


Physical structure of transcriptional regulation

We are investigating how transcriptional regulation is genetically encoded. In particular, we are interested in understanding how the behavior of a gene circuit is determined by its physical encoding within the genome. By physical encoding, we mean the orientation and relative proximity of a transcription factor to its target structural genes. We have shown that, in addition to the specific regulatory mechanism employed, the behavior of a gene circuit may also be determined by how it is physically encoded within the genome. In particular, we found that the sensitivity and metabolic cost associated with an inducible gene circuit can be altered by different genetic encodings. These results are significant because they are among the first to demonstrate how different encodings of otherwise equivalent gene circuits can affect their behavior.

The role of configuration and coupling in autoregulatory gene circuits.
Molecular Microbiology, 75(2):513-27, 2010
Wu K, Rao CV
PubMed PDF

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