IMAGiNE:Dissecting neuronal and systemic responses to interacting environmental stressors

Exposure to environmental chemicals can be harmful to ecosystems and organisms, including humans. One type of chemical can produce Reactive Oxygen Species (ROS), which are forms of oxygen that damage cells. Animals respond to ROS by escaping and producing molecules that degrade ROS as a defense mechanism. Laboratory experiments typically focus on analyzing animal responses to a single chemical, but realistic scenarios involve mixtures of multiple chemicals. Observed effects due to manipulating a single chemical could be heightened or silenced when mixtures of chemicals are considered. This project focuses on understanding how animals respond to mixtures of chemicals that produce ROS using nematodes as a model organism. Key questions include how different responses in the organism change with time, and whether the nervous system is important in generating such responses. Understanding whether different conditions and chemical mixtures result in different responses also is a key objective. This work will build understanding about how animals respond to environmental chemicals in realistic scenarios, which is important to understand the effects of such exposures on the health of humans and other species. This project also serves to develop several tools useful for the broader scientific community, such as tools for measuring escape responses in nematodes and the generation of defense enzymes. In addition, this project includes training of a diverse workforce in the biological sciences as it interfaces with data science and statistics. Finally, the outreach program associated with the project focuses on engaging with high school students from under-represented groups in STEM.

Different types of noxious environments can drive the stress response and act through closely associated genetic pathways. Most studies focus on exposure to single stressors and measure responses from a single organismal readout. Yet, realistic environmental exposures consist of complex mixtures through long periods of time. How multiple stressors interact to drive the stress response in a time-dependent manner, and how diverse responses from different cells and tissues orchestrate the organismal response is not fully understood. A challenge to address these questions is the need to acquire responses from multiple levels of the organism, and to perform a broad range of combinatorial exposures that can probe a wide organismal stress response space. This work uses the model organism C. elegans to answer: 1. Whether oxidants and other stressors exhibit interacting effects on the stress response; and 2. Whether oxidant detection plays a role in the organismal oxidative stress response, and if so, whether neuronal and transcriptional programs operate in different contexts and time scales. This work determines whether different response modalities are elicited by different exposures, involves measurement of responses from multiple biological units (neuron signaling, transcription factor activity, and antioxidant enzyme gene expression) with tissue specificity, and includes development of data-driven models to identify functional relationships between different stress-response signals in the organism. A large focus of this work is on assessing the responses to combinations of chemical mixtures, and on studying the dynamics of the organismal responses. The project goals are achieved through integration of several complementary approaches, including microfluidics, fluorescence imaging, optogenetics, neuronal silencing, and statistical modeling.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.