Role of the Integrator complex in cell surveillance and protection to environmental stress in C. elegans

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Heavy metals such as cadmium are widespread environmental contaminants that are commonly found in Canada and are hazardous to animals and humans. Despite decades of research, the basic mechanisms of cadmium toxicity remain vague. To study the toxicology of heavy metal compounds, my lab uses the roundworm Caenorhabditis elegans as a model system. The C. elegans model comes with an extensive genetic toolkit that allows researchers to study in depth the toxic effects of a given compound on cell physiology while integrating cutting-edge gene manipulation techniques. My recent work has shown that exposure to the heavy metal cadmium in C. elegans can cause damage to the Integrator complex, which is an evolutionarily conserved protein structure that regulates many aspects of RNA metabolism. Damages to the Integrator can lead to RNA processing errors that are toxic to living cells, which at the whole-organism level, can develop into more serious consequences including shortened lifespan, decrease in reproduction, and compromised stress resistance. ******My research to date hypothesizes that damages to the Integrator represent a novel mechanism of cadmium toxicity. I propose that studying the regulation of the Integrator may reveal new insight into the mode of action of cadmium toxins and, in a broader scope, general mechanisms of heavy metal toxicity. The long-term goal of my research program is to uncover how genes and proteins interact with toxins in our environment, and the consequences these interactions have on animal physiology (e.g. aging, development, and reproduction). This proposal seeks to uncover how the Integrator, and its underlying regulatory networks, interact with heavy metal compounds to influence cell and animal physiology. To accomplish this goal, my research group will use a combination of experimental approaches including molecular biology, protein biochemistry, and animal physiology. The short-term objectives of this proposal are to (i) characterize how the Integrator is controlled under periods of stress, (ii) define where and how cadmium damages the Integrator to disrupt cell stability, and (iii) identify the consequences of cadmium mediated Integrator damage on RNA metabolism. ******The outcome of this research will have an immediate impact on basic science by improving the current molecular understanding of heavy metal toxicity. As heavy metals are hazardous to animals and humans, this research program will also have biomedical relevance by uncovering gene factors that are important for toxicity resistance. From an applied perspective, this research can increase public knowledge on toxicities of environmental contaminants, and inform Canadian regulators to improve on current heavy metal safety guidelines. Importantly, this interdisciplinary research program will provide outstanding training to prepare highly-qualified personnel with expertise to support and lead Canada as a world leader in the field of stress biology and toxicology.**