CAREER: Using C. elegans to Understand how a Fundamental Cellular Stress Response is Integrated into a Tissue System at the Interface with the Environment and to Improve Education

职业：利用线虫了解基本细胞应激反应如何整合到与环境接触的组织系统中并改善教育

• 批准号: 1452948
• 负责人: Keith Choe
• 金额: $ 75.41万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1452948&HistoricalAwards=false
• 关键词: CAREER; Using; C.; elegans; Understand

Very little is known about how extracellular matrix barriers and inducible cytoprotective transcription factors function together to detect environmental stress and promote homeostasis. The nematode Caenorhabditis elegans has a single antioxidant/detoxification response transcription factor named SKN-1. The principle investigator of this award has made the surprising discovery that osmotic and genetic distortion of the cuticle activates several SKN-1- dependent cytoprotective genes and that SKN-1 strongly influences cuticle structure and expression of cuticle remodeling genes. The central hypothesis for the research in this CAREER award is that SKN-1 is activated by a cuticle associated environmental stress sensor and that SKN-1, in turn, directs or modifies cuticle synthesis or remodeling during stress or aging. Nematode parasites damage 80 billion dollars worth of crops each year, burden animal husbandry, and infect 1/3 of humans world-wide. Therefore, this project is an important starting point for a basic understanding of how SKN-1 and the nematode cuticle interact to influence resistance to pesticides, anti-parasitic drugs, and plant and animal host-immune responses. A new advanced research course will train a generation of beginning scientists on molecular genetics research and foster collaboration among seven C. elegans laboratories studying a broad range of topics. Additional outreach activities will directly improve STEM training and literacy for high school students and teachers, many from predominantly underserved communities. SKN-1 and its homologs are master regulators of cytoprotective genes that promote stress resistance and longevity throughout the animal kingdom. The study objectives are to leverage molecular and genetic approaches in C. elegans to: 1) identify osmotic signaling from the cuticle to SKN-1; 2) investigate whether, why, and how SKN-1 modifies the cuticle; 3) develop C. elegans learning modules and a teacher workshop; and 4) teach an advanced C. elegans research course for beginning scientists from seven labs. Biochemical assays, RNA interference approaches, transcript profiling, histologic and ultrastructure analyses, and genetic studies will be performed to achieve these objectives. Osmolarity is one of the most broadly shared and ancient forms of homeostasis. This project will provide novel genetic and molecular insights into osmo-sensing and signal transduction. For many of the same reasons that it is a powerful research model (e.g., simple and inexpensive, but permits sophisticated genetic and molecular approaches), C. elegans has tremendous unmet potential in education. The PI will collaborate with an institutional pre-collegiate training program and high school teachers to develop and implement learning modules and training workshops that utilize RNA interference and green fluorescent protein technologies to stimulate interest in gene regulation and demonstrate broad application of basic research. Results from the studies will be published in peer-reviewed journals and presented at regional and national scientific meetings.

关于细胞外基质屏障和诱导型细胞保护性转录因子如何共同发挥作用以检测环境应激和促进体内平衡，我们知之甚少。秀丽隐杆线虫（Caelophabditis elegans）有一个单一的抗氧化/解毒反应转录因子，命名为SKN-1。该奖项的主要研究者做出了令人惊讶的发现，角质层的渗透和遗传畸变激活了几个SKN-1依赖的细胞保护基因，SKN-1强烈影响角质层结构和角质层重塑基因的表达。这项研究的中心假设是，SKN-1是由角质层相关的环境压力传感器激活的，而SKN-1反过来又会在压力或衰老过程中指导或修改角质层的合成或重塑。线虫寄生虫每年破坏价值800亿美元的农作物，给畜牧业带来负担，并感染全世界1/3的人类。因此，该项目是基本了解SKN-1和线虫角质层如何相互作用以影响对农药，抗寄生虫药物以及植物和动物宿主免疫反应的重要起点。一个新的高级研究课程将培养一代分子遗传学研究的初级科学家，并促进七个C。elegans实验室研究广泛的主题。额外的推广活动将直接改善高中学生和教师的STEM培训和扫盲，其中许多人来自服务不足的社区。SKN-1及其同源物是细胞保护基因的主要调节因子，这些基因在整个动物王国中促进应激抗性和长寿。本研究的目的是利用分子和遗传学方法在C. elegans：1）鉴定从角质层到SKN-1的渗透信号; 2）研究SKN-1是否、为什么以及如何修饰角质层; 3）开发C. elegans学习模块和教师工作坊;以及4）教授高级C。为来自七个实验室的科学家开设的优雅研究课程。将进行生化测定、RNA干扰方法、转录谱分析、组织学和超微结构分析以及遗传研究以实现这些目标。渗透压是最广泛共享和古老的稳态形式之一。该项目将提供新的遗传和分子的见解，传感器和信号转导。由于许多相同的原因，它是一个强大的研究模型（例如，简单和廉价，但允许复杂的遗传和分子方法），C。elegans在教育方面有着巨大的潜力。PI将与一个大学预科培训项目和高中教师合作，开发和实施利用RNA干扰和绿色荧光蛋白技术的学习模块和培训讲习班，以激发对基因调控的兴趣，并展示基础研究的广泛应用。研究结果将发表在同行评审的期刊上，并在区域和国家科学会议上发表。