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环境污染物，对动物和人类有害。尽管经过几十年的研究，镉毒性的基本机制仍然模糊不清。为了研究重金属化合物的毒理学，我的实验室使用线虫作为模型系统。梭elegans模型带有一个广泛的遗传工具包，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。我最近的研究表明，C.线虫可导致整合子复合物的损伤，整合子复合物是一种进化上保守的蛋白质结构，调节RNA代谢的许多方面。对整合子的损害可能导致对活细胞有毒的RNA加工错误，这在整个生物体水平上可能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，我的研究假设对整合子的损害代表了镉毒性的一种新机制。我建议，研究的集成商的监管可能会揭示新的见解镉毒素的作用模式，并在更广泛的范围内，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。该提案旨在揭示整合剂及其潜在的调控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，我的研究小组将使用包括分子生物学，蛋白质生物化学和动物生理学在内的实验方法。本提案的短期目标是（i）表征在应激期间如何控制整合剂，（ii）确定镉在何处以及如何损害整合剂以破坏细胞稳定性，以及（iii）确定镉介导的整合剂损害对RNA代谢的后果。 这项研究的结果将通过改善目前对重金属毒性的分子理解对基础科学产生直接影响。由于重金属对动物和人类有害，这项研究计划还将通过揭示对毒性抗性重要的基因因素来具有生物医学意义。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，并为加拿大监管机构提供信息，以改善目前的重金属安全指南。重要的是，这个跨学科的研究计划将提供优秀的培训，准备高素质的专业人才，以支持和领导加拿大作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.