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 and Center have 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) controlled by the transcription factor Nrf2. 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. Furthermore, dietary components including marine algae (seaweed) that activate Nrf2 have demonstrated anti-inflammatory activity in vivo and potential for the treatment or prevention of inflammatory diseases of the digestive tract, with concomitant beneficial modulation of the gut microbiome. In cancer cells, however, Nrf2 can mediate resistance to chemotherapy, and in parallel we performed screening campaigns to identify novel druggable targets and inhibitors of Nrf2 towards overcoming drug resistance. Similarly approaches are taken with other transcription factors of interest, including NFkB and HIF.
- Bousquet, M. S.; Ratnayake, R.; Pope, J. L.; Chen, Q.-Y.; Zhu, F; Chen, S.; Carney, T. J.; Gharaibeh, R. Z.; Jobin, C.; Paul, V. J.; Luesch, H. “Seaweed Natural Products Modify the Host Inflammatory Response via Nrf2 Signaling and Alter Colon Microbiota Composition and Gene Expression” Free Rad. Biol. Med. 2020, 146, 306–323. ncbi.nlm.nih.gov/pubmed/31536771
- Matthews, J. H.; Liang, X.; Paul, V. J.; Luesch, H. “A Complementary Chemical and Genomic Screening Approach for Druggable Targets in the Nrf2 Pathway and Small Molecule Inhibitors to Overcome Cancer Cell Drug Resistance” ACS Chem. Biol. 2018, 13, 1189–1199. ncbi.nlm.nih.gov/pubmed/29565554
- Bousquet, M. S.; Ma, J. J.; Ratnayake, R.; Havre, P. A.; Yao, J.; Dang, N. H.; Paul, V. J.; Carney, T. J.; Dang, L. H.; Luesch, H. “Multidimensional Screening Platform for Simultaneously Targeting Oncogenic KRAS and Hypoxia-Inducible Factors Pathways in Colorectal Cancer” ACS Chem. Biol. 2016, 11, 1322–1331. ncbi.nlm.nih.gov/pubmed/26938486
- 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. ncbi.nlm.nih.gov/pubmed/23773140
- Ratnayake, R.; Liu, Y.; Paul, V. J.; Luesch, H. “Cultivated Sea Lettuce is a Multiorgan Protector from Oxidative and Inflammatory Stress by Enhancing the Endogenous Antioxidant Defense System” Cancer Prev. Res. 2013, 6, 989‒999. ncbi.nlm.nih.gov/pubmed/24005795
- Wang, R.; Paul, V. J.; Luesch, H. “Seaweed Extracts and Unsaturated Fatty Acid Constituents from the Green Alga Ulva lactuca as Activators of the Cytoprotective Nrf2‒ARE Pathway” Free Radic. Biol. Med. 2013, 57, 141‒153. ncbi.nlm.nih.gov/pubmed/23291594
- 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” Nature Cell Biol. 2010, 12, 758–767. ncbi.nlm.nih.gov/pubmed/20622870
- 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” Biol. 2010, 17, 537–547. ncbi.nlm.nih.gov/pubmed/20534351
- Luesch, H.; Liu, Y. “Genome-Wide Overexpression Screen for Activators of Antioxidant Gene Transcription” Methods Mol. Biol. 2008, 477, 343–354. ncbi.nlm.nih.gov/pubmed/19082959
- 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” Natl. Acad. Sci. USA 2007, 104, 5205–5210. ncbi.nlm.nih.gov/pubmed/17360324
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