Functional Genomics and High-Throughput Screening
In parallel efforts, we are carrying out studies to reveal the function and action of genes/proteins that are putatively involved in cancer, aging and neurodegeneration. Candidate genes identified by high-throughput genome-wide cDNA and RNAi screening are subjected to molecular and biological characterization including structure-function studies in cell- and animal-based models. The ultimate goal is to modulate gene or protein function with small molecules which could then be translated into valuable chemical biology tools or even novel drugs. Our lab has the infrastructure to run HTS campaigns in 384-well plate format in semi-automated fashion.
One focus of ours has been on gene products that modulate oxidative stress levels through activation of the antioxidant response element (ARE). In humans, the ARE regulates the expression of a number of cytoprotective antioxidant enzymes and scavengers which contribute to the endogenous defense against oxidative stress. The activation of the ARE in the absence of general oxidative stress could provide a novel therapeutic approach for the treatment of various neurodegenerative diseases, stroke and aging. Consequently, we are also screening large-scale or focused synthetic libraries as well as natural products for small molecule modulators of target or pathway activity.
Liu, Y.; Kern, J. T.; Walker, J. R.; Johnson, J. A.; Schultz, P. G.; Luesch, H. “A Genomic Screen for Activators of the Antioxidant Response Element” Proc. Natl. Acad. Sci. USA 2007, 104, 5205–5210.
Luesch, H.; Liu, Y. “Genome-Wide Overexpression Screen for Activators of Antioxidant Gene Transcription” Methods Mol. Biol. 2008, 477, 343–354.
Wang, R.; Kern, J. T.; Goodfriend, T. L.; Ball, D. L.; Luesch, H. “Activation of the Antioxidant Response Element by Specific Oxidized Metabolites of Linoleic acid” Prostaglandins Leukotrienes Essent. Fatty Acids 2009, 81, 53–59.
Hur, W.; Sun, Z.; Jiang, T.; Mason, D. E.; Peters, E. C.; Zhang, D. D.; Luesch, H.; Schultz, P. G.; Gray, N. S. “A Small-Molecule Inducer of the Antioxidant Response Element” Chem. Biol. 2010, 17, 537–547.
Teo, H.; Ghosh, S.; Luesch, H.; Ghosh, A.; Wong, E. T.; Malik, N.; Orth, A.; de Jesus, P.; Perry, A. S.; Oliver, J. D.; Tran, N. L.; Speiser, L. J.; Wong, M.; Saez, E.; Schultz, P.; Chanda, S. K.; Verma, I. M.; Tergaonkar, V. “Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression” Nat. Cell Biol. 2010, 12, 758–767.
Wang, R.; Mason, D. E.; Choe, K. P.; Lewin, A. S.; Peters, E. C.; Luesch, H. “In Vitro and in Vivo Characterization of a Tunable Dual-Reactivity Probe of the Nrf2-ARE Pathway” ACS Chem. Biol. 2013, 8, 1764‒1774.
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