CAREER: Using C. elegans to Understand how a Fundamental Cellular Stress Response is Integrated into a Tissue System at the Interface with the Environment and to Improve Education

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Very little is known about how extracellular matrix barriers and inducible cytoprotective transcription factors function together to detect environmental stress and promote homeostasis. The nematode Caenorhabditis elegans has a single antioxidant/detoxification response transcription factor named SKN-1. The principle investigator of this award has made the surprising discovery that osmotic and genetic distortion of the cuticle activates several SKN-1- dependent cytoprotective genes and that SKN-1 strongly influences cuticle structure and expression of cuticle remodeling genes. The central hypothesis for the research in this CAREER award is that SKN-1 is activated by a cuticle associated environmental stress sensor and that SKN-1, in turn, directs or modifies cuticle synthesis or remodeling during stress or aging. Nematode parasites damage 80 billion dollars worth of crops each year, burden animal husbandry, and infect 1/3 of humans world-wide. Therefore, this project is an important starting point for a basic understanding of how SKN-1 and the nematode cuticle interact to influence resistance to pesticides, anti-parasitic drugs, and plant and animal host-immune responses. A new advanced research course will train a generation of beginning scientists on molecular genetics research and foster collaboration among seven C. elegans laboratories studying a broad range of topics. Additional outreach activities will directly improve STEM training and literacy for high school students and teachers, many from predominantly underserved communities. SKN-1 and its homologs are master regulators of cytoprotective genes that promote stress resistance and longevity throughout the animal kingdom. The study objectives are to leverage molecular and genetic approaches in C. elegans to: 1) identify osmotic signaling from the cuticle to SKN-1; 2) investigate whether, why, and how SKN-1 modifies the cuticle; 3) develop C. elegans learning modules and a teacher workshop; and 4) teach an advanced C. elegans research course for beginning scientists from seven labs. Biochemical assays, RNA interference approaches, transcript profiling, histologic and ultrastructure analyses, and genetic studies will be performed to achieve these objectives. Osmolarity is one of the most broadly shared and ancient forms of homeostasis. This project will provide novel genetic and molecular insights into osmo-sensing and signal transduction. For many of the same reasons that it is a powerful research model (e.g., simple and inexpensive, but permits sophisticated genetic and molecular approaches), C. elegans has tremendous unmet potential in education. The PI will collaborate with an institutional pre-collegiate training program and high school teachers to develop and implement learning modules and training workshops that utilize RNA interference and green fluorescent protein technologies to stimulate interest in gene regulation and demonstrate broad application of basic research. Results from the studies will be published in peer-reviewed journals and presented at regional and national scientific meetings.