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

积分器复合体在细胞监测和保护秀丽隐杆线虫环境应激中的作用

• 批准号: RGPIN-2019-04486
• 负责人: Wu, ChengWei
• 金额: $ 2.7万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=737657
• 关键词: Role; Integrator; complex; cell; surveillance

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.

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，尽管经过数十年的研究，镉毒性的基本机制仍然模糊。线虫模型系统 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，同时整合尖端基因。我最近的工作表明，接触线虫中的重金属镉会导致整合蛋白复合物受损，整合蛋白复合物是一种进化上保守的蛋白质结构，可调节 RNA 代谢的许多方面。对整合蛋白的损害可能会导致 RNA 加工错误。对活细胞有毒，在整个生物体水平上，可能会产生更严重的后果，包括寿命缩短、繁殖减少和抗压能力受损，迄今为止，损害集成器的陷阱代表了一种新机制。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。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的影响（例如衰老、发育和繁殖）。该提案旨在揭示整合器及其基础调控网络如何与重金属相互作用。化合物到为了实现这一目标，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) 描述积分器的特征。 (ii) 确定镉在何处以及如何损害 Integrator 从而破坏细胞稳定性，以及 (iii) 确定镉介导的 Integrator 损害对 RNA 代谢的影响。这项研究的结果将对 RNA 代谢产生直接影响。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至关重要的基因因素来提高基础科学的相关性。增加公众对环境污染物毒性的了解，并告知加拿大监管机构改进当前的重金属安全指南。重要的是，这一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世界领先者。应激生物学领域和毒理学。