Jian Cao

Bristol-Myers Squibb, New York City, New York, United States

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Publications (2)13 Total impact

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    ABSTRACT: Author Summary Transcriptional profiling is arguably the most powerful hypothesis-free method for investigating biological effects of drugsā€”so why do the experiments typically use outmoded single-dose designs? Such single-dose experiments will co-mingle effects that can occur with different potency (e.g., effects on the known target versus effects on additional undesired targets). Single-dose experiments have little comparability to the dose-response bioassays, which are now used throughout the drug discovery processes. One reason for the disparity between experimental approaches is that existing analytical methods for dose-response bioassays can't cope with the dimensionality of microarray data: a typical bioassay is optimized for one response, then used to run a screen against thousands of compounds; whereas transcriptional profiling measures thousands of non-optimized responses to a single compound. Conversely, existing methods for microarray data analysis can identify patterns, but provide no quantitative dose-response information. To overcome these problems, we developed novel algorithms and visualization methods that allow anyone to apply transcriptional profiling as a conventional dose-response assay. The approach provides far more information than limited-dose designs, yet is economical (12 arrays/compound). With this new analytical framework, it is now possible to identify distinct transcriptional responses at distinct regions of the dose range, to link these impacts to biological pathways, and to make realistic connections to drug targets and to other bioassays.
    PLoS Computational Biology 09/2009; 5(9):e1000512. DOI:10.1371/journal.pcbi.1000512 · 4.83 Impact Factor
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    ABSTRACT: We report here on a chemical genetic screen designed to address the mechanism of action of a small molecule. Small molecules that were active in models of urinary incontinence were tested on the nematode Caenorhabditis elegans, and the resulting phenotypes were used as readouts in a genetic screen to identify possible molecular targets. The mutations giving resistance to compound were found to affect members of the RGS protein/G-protein complex. Studies in mammalian systems confirmed that the small molecules inhibit muscarinic G-protein coupled receptor (GPCR) signaling involving G-alphaq (G-protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-alphaq signaling complex, and define new mutations in both RGS and G-alphaq, including a unique hypo-adapation allele of G-alphaq. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation.
    PLoS Genetics 05/2006; 2(4):e57. DOI:10.1371/journal.pgen.0020057 · 8.17 Impact Factor