Collaborative Research: Understanding the molecular diversification of self recognition through ray-finned fish innate immune receptor families

生物体识别入侵病原体、感染细胞或癌细胞并杀死它们而不对自身造成过度损害的能力是生存所必需的。从鱼类到青蛙再到人类，地球上所有约60，000种脊椎动物都使用复杂的免疫细胞来“检查”体内的每一个其他细胞，以确定它是朋友还是敌人。这些免疫细胞在其表面上具有大量的蛋白质受体，这些受体致力于维持和平。这些受体中的许多被设计为识别特定类型的病原体，形成防御的前线。然而，病原体通常繁殖迅速，使它们比大多数脊椎动物进化或变化更快，从而发展出逃避检测的方法。作为回应，脊椎动物进化出了一个复杂的免疫系统，其中包括大量的受体，这些受体比大多数其他蛋白质进化得更快，并且专门针对预期和未预期的病原体。鱼类占所有脊椎动物的一半，作为一个群体，是研究这些防御遗传基础的重要模型。该项目将使用来自许多鱼类的新的和现有的基因组数据来确定这些受体的起源，并研究这些受体如何进化以实现今天观察到的多样性。以鱼类为模型，这项工作将揭示所有脊椎动物免疫的基本方面。从这个项目收集的数据将被纳入北卡罗来纳州自然科学博物馆的多个新展览中。射线鳍鱼（Actinopenned fish）占地球上现存脊椎动物的一半以上，使它们成为了解免疫基因遗传和功能进化的强大系统。鱼类不仅与哺乳动物共享某些免疫基因家族，而且编码许多高度多样的“鱼类特异性”免疫基因家族。了解免疫相关基因家族多样化的基础因素对于解释新基因的起源和亚/新功能化以及了解病原体识别和抗性的分子基础至关重要。为了深入了解脊椎动物免疫基因家族的起源及其多样性动态，本项目将整合系统发育比较框架与新的和现有的转录组和基因组序列数据从多个鳍鱼谱系，以确定基因组结构如何影响基因家族进化的速率和机制。本项目还将评估自我基因编码标记及其候选受体之间的相互依赖性。总的来说，这个项目将阐明识别机制的演变，在所有的鳍鱼从非自我描绘自我，并揭示新的见解保守和不同的手段来实现这一重要的免疫功能。最后，该项目将在北卡罗来纳州自然科学博物馆创建媒体内容和互动展览，包括虚拟现实和增强现实视频游戏，向游客传授免疫系统如何发挥作用的基本方面。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。

The ability of an organism to recognize invading pathogens, infected cells, or cancerous cells and kill them without causing excessive damage to itself is essential for survival. From fish to frogs to humans, all of the ~60,000 vertebrate species on earth use sophisticated immune cells to "inspect" every other cell in their body to determine if it is friend or foe. These immune cells possess a large number of protein receptors on their surface that work to maintain the peace. Many of these receptors are designed to recognize specific types of pathogens, forming a front line of defense. However, pathogens typically reproduce quickly, allowing them to evolve or change faster than most vertebrates and thereby develop ways to escape detection. In response, vertebrates have evolved a complex immune system that includes large groups of receptors that evolve faster than most other proteins and are specialized for anticipated as well as unanticipated pathogens. Fish represent half of all vertebrates and, as a group, are a great model for studying the genetic basis of these defenses. This project will use new and existing genomic data from numerous fish species to determine the origins of these receptors and study how these receptors have evolved to achieve the diversity observed today. Using fish as a model, this work will reveal fundamental aspects of immunity in all vertebrates. Data collected from this project will be incorporated into multiple new exhibits at the North Carolina Museum of Natural Sciences.Ray-finned fish (Actinopterygii) constitute over half of the extant vertebrates on earth, making them a powerful system for understanding the genetic and functional evolution of immune genes. Fish not only share certain immune gene families with mammals, but also encode a number of highly diverse "fish-specific" immune gene families. Understanding the factors that underlie the diversification of gene families involved in immunity is critical for explaining the origins and sub-/neo-functionalization of new genes and for understanding the molecular basis of pathogen recognition and resistance. In order to provide an in-depth understanding of the origins of vertebrate immune gene families and their diversification dynamics, this project will integrate a phylogenetic comparative framework with new and existing transcriptome and genomic sequence data from multiple ray-finned fish lineages to determine how genomic architecture impacts the rate and mechanism of gene family evolution. This project will also evaluate the interdependence between genetically encoded markers of self and their candidate receptors. In total, this project will illuminate the evolution of recognition mechanisms that delineate self from non-self in all ray-finned fish, and reveal novel insight into both conserved and divergent means of accomplishing this critical immune function. Finally, this project will enable the creation of media content and interactive exhibits at the North Carolina Museum of Natural Sciences including a virtual reality and augmented reality video-game that teaches visitors fundamental aspects of how immune systems function.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.