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

镉等重金属是加拿大常见的广泛环境污染物，对动物和人类有害。尽管经过数十年的研究，镉毒性的基本机制仍然模糊。为了研究重金属化合物的毒理学，我的实验室使用线虫秀丽隐杆线虫作为模型系统。线虫模型配备了广泛的遗传工具包，使研究人员能够深入研究给定化合物对细胞生理学的毒性作用，同时整合尖端的基因操作技术。我最近的工作表明，接触线虫体内的重金属镉会对整合复合体造成损害，整合复合体是一种进化上保守的蛋白质结构，调节 RNA 代谢的许多方面。 Integrator 的损坏可能会导致 RNA 处理错误，对活细胞有毒，在整个生物体水平上，可能会发展成更严重的后果，包括寿命缩短、繁殖减少和抗应激能力受损。 迄今为止，我的研究假设积分器的损坏代表了镉毒性的一种新机制。我建议研究积分器的调节可能会揭示镉毒素作用模式的新见解，并在更广泛的范围内揭示重金属毒性的一般机制。我的研究计划的长期目标是揭示基因和蛋白质如何与我们环境中的毒素相互作用，以及这些相互作用对动物生理学（例如衰老、发育和繁殖）的影响。该提案旨在揭示积分器及其底层监管网络如何与重金属化合物相互作用以影响细胞和动物生理学。为了实现这一目标，我的研究小组将结合使用分子生物学、蛋白质生物化学和动物生理学等实验方法。该提案的短期目标是 (i) 描述在应激期间如何控制积分器，(ii) 确定镉在何处以及如何损坏积分器以破坏细胞稳定性，以及 (iii) 确定镉介导的积分器损伤对 RNA 代谢的后果。 这项研究的结果将通过提高目前对重金属毒性的分子理解而对基础科学产生直接影响。由于重金属对动物和人类有害，该研究项目还将通过揭示对毒性抵抗重要的基因因素而具有生物医学意义。从应用的角度来看，这项研究可以增加公众对环境污染物毒性的认识，并告知加拿大监管机构改进现行的重金属安全指南。重要的是，这个跨学科研究计划将提供出色的培训，培养具有专业知识的高素质人员，以支持和领导加拿大成为应激生物学和毒理学领域的世界领导者。

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.