RUI: Integration of the Epithelial Innate Immune and Oxidative Stress Responses

动物与各种微生物相互作用。有些微生物是致病的，会引起疾病。其他良性微生物，如微生物群，是与动物相关的正常菌群的一部分。因此，免疫系统必须使用一种微妙的检测系统，区分致病微生物和良性微生物。免疫系统检测病原微生物的一种方式是通过宿主细胞损伤和应激的存在。本项目旨在剖析感染的分子和遗传机制，从保守的G蛋白偶联受体FSHR-1开始，以及该受体的激活如何导致氧化应激。为了产生更广泛的影响，部分实验将在基于本科课程的研究体验的背景下进行，让大约100名本科生沉浸在真实的研究项目中。这项研究为下一代科学家提供了培训。有大量研究的学生将成为以研究为基础的出版物的共同作者。与感染相关的一种压力是氧化应激。然而，氧化应激和感染识别之间的直接联系尚未建立。这就是本研究项目的目标。在秀丽线虫中，保守的G蛋白偶联受体FSHR-1在天然免疫和氧化应激反应中都起着关键作用，是协调这两个关键过程的主要候选者。这些实验将利用遗传上位性建立FSHR-1与受感染动物氧化应激反应的主要分子成分之间的关系(目标1)。免疫反应的多种测量将评估氧化应激是否是识别感染的必要和/或充分因素(目标2)。最后，将确定连接氧化应激和免疫的新基因，以构建一个更完整的框架，以整合这些过程(目标3)。这项研究项目有可能改变人们对使用实验上易于处理的系统检测感染的分子机制的理解。深入了解免疫和氧化应激之间的联系，以及FSHR-1‘S在其中的作用，不仅将揭示区分致病微生物和良性微生物的新方法，而且还将为动物与其自然微生物环境之间的相互作用提供有价值的见解。此外，这项研究提供了一个平台，允许本科生研究人员进行基于假设的研究，作为培养下一代科学家的一种手段。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Animals interact with diverse microorganisms. Some microbes are pathogenic, and cause disease. Other benign microbes, like the microbiome, are part of the normal flora associated with the animal. The immune system must therefore use a nuanced detection system that discriminates between pathogenic and benign microbes. One way the immune system detects pathogenic microbes is by the presence of host cell damage and stress. This project seeks to dissect the molecular and genetic mechanism of infection that start with the conserved G-protein Coupled Receptor FSHR-1 and how this receptor activation results in oxidative stress. For broader impacts, a portion of the experiments will be performed in the context of an undergraduate course-based research experience, immersing approximately 100 undergraduate students in authentic research projects. This research provides training for the next generation of scientists. Students with substantial research will be co-authors on research-based publications. One type of stress associated with infection is oxidative stress. However, a direct link between oxidative stress and infection recognition has not been established. This is the goal of this research project. The conserved G-protein Coupled Receptor FSHR-1 is a key player in both innate immunity and the response to oxidative stress, and is a primary candidate to coordinate these two critical processes in Caenorhabditis elegans. The experiments will establish the relationship between FSHR-1 and principal molecular components of the oxidative stress response in infected animals using genetic epistasis (Aim 1). Multiple measures of the immune response will assess whether oxidative stress is a necessary and/or sufficient element of infection recognition (Aim 2). Finally, novel genes that connect oxidative stress and immunity will be identified to construct a more complete framework for the integration of these processes (Aim 3). This research project has the potential to transform understanding of the molecular mechanisms by which infection is detected using an experimentally tractable system. Insight into the connection between immunity and oxidative stress, and FSHR-1's role therein, will not only reveal a new means for differentiating pathogenic vs. benign microbes, but will also provide valuable insights into the interaction between animals and their natural microbial milieu. In addition, this research provides a platform that allows undergraduate researchers to perform hypothesis-based research as a means to train the next generation of scientists.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.