Molecular mechanism of a toxin-antidote system

毒素解毒系统的分子机制

• 批准号: 2344838
• 负责人: Michael Ailion
• 金额: $ 108.1万
• 依托单位: University of Washington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2344838&HistoricalAwards=false
• 关键词: Molecular; mechanism; toxin; antidote; system

This project investigates the molecular mechanisms underlying the action of a genetic element in nematode worms that leads to reproductive isolation, an initial step in the evolution and origin of new species. This research will be complemented by the isolation and identification of new worm strains and species from nature by a large number of high school students, providing the raw material for future studies of related genetic elements. Students will benefit by learning how research is performed and will gain a basic understanding of genes, DNA, and evolution that is becoming increasingly more important and societally relevant. By engaging students in the practice of science, this project fulfills one of the three central dimensions in the Next Generation Science Standards recently adopted by many states across the nation to reform science education and will improve scientific literacy by helping to build an informed public that understands the scientific enterprise and can better contribute to future national policy decisions that require the interpretation and evaluation of scientific data. The project will also provide direct training in research for graduate, undergraduate, and high school students.This research focuses on investigating how a selfish genetic element consisting of a toxin and antidote acts at the cellular and molecular levels. The peel-1/zeel-1 system in the nematode C. elegans includes a toxin that kills cells unless counteracted by its antidote. This project aims to determine how the PEEL-1 toxin kills cells and how the ZEEL-1 antidote acts to prevent cell death. The project will test whether PEEL-1 kills cells by co-opting the small transmembrane protein PMPL-1 to form a toxic ion channel or membrane pore that leads to cell death due to osmotic dysregulation, and whether ZEEL-1 opposes this activity by facilitating the ubiquitylation and subsequent degradation of PEEL-1 or PMPL-1. The research will use C. elegans, HEK293T cells as a reconstituted heterologous system, and biochemical experiments using purified proteins.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.

该项目研究了线虫中遗传元件作用的分子机制，该遗传元件导致生殖隔离，这是新物种进化和起源的第一步。这项研究将辅之以大量高中生从自然界中分离和鉴定新的蠕虫品系和物种，为未来相关遗传元件的研究提供原材料。学生将受益于学习如何进行研究，并将获得对基因、DNA 和进化的基本了解，这些知识变得越来越重要且与社会相关。通过让学生参与科学实践，该项目实现了全国许多州最近为改革科学教育而采用的下一代科学标准的三个核心维度之一，并将通过帮助建立了解科学事业的知情公众来提高科学素养，并更好地为需要解释和评估科学数据的未来国家政策决策做出贡献。该项目还将为研究生、本科生和高中生提供直接的研究培训。这项研究的重点是研究由毒素和解毒剂组成的自私遗传元素如何在细胞和分子水平上发挥作用。线虫秀丽隐杆线虫中的peel-1/zeel-1系统含有一种毒素，除非有解毒剂抵消，否则该毒素会杀死细胞。该项目旨在确定 PEEL-1 毒素如何杀死细胞以及 ZEEL-1 解毒剂如何防止细胞死亡。该项目将测试PEEL-1是否通过选择小跨膜蛋白PMPL-1形成有毒离子通道或膜孔，导致细胞因渗透压失调而死亡，从而杀死细胞，以及ZEEL-1是否通过促进PEEL-1或PMPL-1的泛素化和随后的降解来对抗这种活性。该研究将使用线虫、HEK293T 细胞作为重建的异源系统，并使用纯化的蛋白质进行生化实验。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。