Fields: Cellular and Molecular Biology
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- Biological Principles: Biology of Aging
- Cell Biology
Energy homeostasis is crucial for survival. Nutrition influences fertility, lifespan, and other fundamental processes. Although the cellular and genetic responses to starvation have been well studied, the response to excess nutrition—or “nutrient stress”—is poorly understood. My lab uses the nematode Caenorhabditis elegans (“the worm”) as a model system to study the molecular, cellular, and genetic responses to glucose stress.
Research in the lab is divided into two broad projects. The first involves characterizing pathways that are known to respond to glucose. I have identified three genes that are necessary for the glucose stress response: the insulin receptor (daf-2 in the worm), the O- GlcNAc transferase (ogt-1) and the O-GlcNAc’ase (oga-1). O-GlcNAc is a post-translational modification derived from glucose, and OGA-1 is a type II diabetes susceptibility locus in humans. OGA-1, OGT-1, and the insulin receptor are essential in mammals but can be studied with temperature-sensitive mutations or knockouts in the worm. Using genetics, molecular biology, and cell biology techniques, we will try to understand how these genes regulate fertility under glucose stress, and whether maternal glucose stress affects subsequent generations.
The second project takes an unbiased approach to identify new genes that connect insulin signaling and glucose stress. Using a daf-2 mutant, I screened an RNAi knockdown library to find genes that decreased insulin signaling in the presence of glucose stress. I identified over 100 candidate genes that are known to be involved in processes including aging, the immune response, protein trafficking, and mitochondrial function. Future projects will determine which of these genes are required for the glucose stress response and elucidate how they regulate insulin signaling.
Picture #1: DAF-16, a transcription factor regulated by insulin signaling, localizes to the nucleus in C. elegans ogt-1 mutants, which we can observe using a DAF-16:GFP fusion protein (photo by Dona Love).
Mondoux MA, Love DC, Ghosh SK, Fukushige T, Bond M, Weerasinghe GR, Hanover JA, and MW Krause. 2011. O-linked-N-acetylglucosamine cycling and insulin signaling are required for the glucose stress response in Caenorhabditis elegans. Genetics 188, 369-82. GET PDF
‡Love, DC, ‡Ghosh, S, ‡Mondoux, MA, Fukushige, T, Wang, P, Wilson, M, Iser, WB, Wolkow, CA, Krause, MW, and JA Hanover. 2010. Dynamic O-GlcNAc cycling at promoters of C. elegans genes regulating longevity, stress, and immunity. PNAS 107(16): 7413-8. GET PDF
Mondoux MA and VA Zakian. 2007. Subtelomeric elements influence but do not determine silencing levels at Saccharomyces cerevisiae telomeres. Genetics 177(4): 2541-6. GET PDF
Mondoux MA, *Scaife, JG, and VA Zakian. 2007. Differential nuclear localization does not determine the silencing status of Saccharomyces cerevisiae telomeres. Genetics 177(4): 2019-29. GET PDF
Baek, K-H, Mondoux, MA, Jaster, R, Fire-Levin, E, and AD D’Andrea. 2001. DUB-2A, A New Member of the DUB Subfamily of Deubiquitinating Enzymes. Blood 98(3): 636-42. GET PDF
Kuang, Y, Garcia-Higuera, I, Moran, A, Mondoux, M, Digweed, M, and AD D’Andrea. 2000. Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity. Blood 96(5): 1625-32. GET PDF
Review Articles & Book Chapters:
Mondoux, MA, Krause, MW, and JA Hanover. 2010. C. elegans Genetic Networks Predict Roles for O-GlcNAc Cycling in Key Signaling Pathways. Current Signal Transduction Therapy. 5(1): 60-73. GET PDF
Mondoux, MA, and VA Zakian. 2006. Telomere Position Effect: Silencing Near the End. in Telomeres, 2nd Edition. Eds. EH Blackburn, T deLange, and V Lundblad. Cold Spring Harbor Laboratory Press. GET PDF
*denotes undergraduate co-author ‡ these authors contributed equally to this work