EiR: Functional Study of the Rapidly Evolving Interferon Complex in Amphibians

目前由于感染导致的两栖动物数量减少对生物多样性和生态系统健康是毁灭性的。干扰素(IFN)是关键的免疫基因，是抗肿瘤和抗病毒反应的重要介质。了解两栖动物IFN的功能对于直接应对导致目前两栖动物数量下降的感染是至关重要的。该项目试图了解两栖类干扰素干扰素在脊椎动物干扰素进化和功能多样化中的标志性作用。IFN起源于多外显子前体的有颌鱼。首席研究员最近的研究发现，在两栖动物中意外出现和扩展了无内含子的干扰素基因。这一发现修正了已建立的干扰素进化模型，并强调了两栖动物对脊椎动物干扰素生物学的研究至关重要。该项目将研究无内含子IFN在青蛙发育过程中的作用和对病毒感染的保护。该项目的完成将提供一个独特的、以前未知的平台，以解决免疫进化、功能能力，特别是两栖动物对病毒感染的防御。该奖项将促进主要研究型大学与历史悠久的黑人学院和大学(HBCU)之间的合作。它将在HBCU提供研究培训并加强生物学教育。关于脊椎动物干扰素基因的分子起源和功能多样性的知识是零散的。特别是，人们对两栖IFN知之甚少。以前的研究只在两栖动物中发现了几个含有内含子的干扰素前体，并且低估了两栖动物中干扰素介导的免疫反应和两栖动物在干扰素进化中的实际作用。作为免疫进化的关键节点，了解两栖类干扰素复合体的功能及其对病原性感染的反应是脊椎动物免疫生物学研究的基础。利用非洲爪蛙实验室模型，本研究将(1)比较分析蛙的发育和感染过程中含内含子和无内含子干扰素亚群的表达，(2)确定新进化的无内含子干扰素对病毒感染的功能能力和进化优势，(3)确定两栖干扰素配体对典型的干扰素信号通路的依赖性，以诱导效应基因和诱导抗病毒活性。这些免费的贡献将从功能上描述两栖动物中的干扰素复合体，并最终填补干扰素进化方面的知识空白。此外，拟议的研究将整合田纳西州立大学(TSU)、范德比尔特大学和罗切斯特大学的PI/Co-Pis的合作努力，以实现这些目标。它将在两个著名的研究机构培训HBCU研究人员，并在少数群体服务的机构加强研究卓越和扩大STEM教育。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。

Current amphibian decline due to infections is devastating for biodiversity and ecosystem health. Interferons (IFNs) are key immune genes that are important mediators of antitumor and antiviral responses. Understanding the function of amphibian IFNs is fundamental to directly addressing infections that are causing current amphibian declines. This project seeks to understand the signature role of amphibian IFNs in IFN evolution and functional diversification in vertebrates. IFNs originated in jawed fish from the multi-exon progenitors. Recent research by the principal investigator detected the unexpected emergence and expansion of intronless IFN genes in amphibians. This discovery revises the established model of IFN evolution and highlights that amphibians are critical for studying IFN biology in vertebrates. This project will examine the role of the intronless IFNs during frog development and protection against viral infection. Completion of this project will provide a unique and previously unknown platform to address immune evolution, functional capacity, and especially amphibian defense against viral infections. This award will promote collaboration between major research universities and a Historically Black College and University (HBCU). It will provide research training and strengthen biology education at the HBCU. Knowledge regarding the molecular origin and functional diversification of IFN genes in vertebrates is fragmentary. In particular, little is known about amphibian IFNs. Previous studies have discovered only several intron-containing IFN progenitors in amphibians and have underestimated IFN-mediated immune responses in amphibians and the actual role of amphibians in IFN evolution. As a key node in immune evolution, functional understanding of amphibian IFN complex and its reaction to pathogenic infections is fundamental to the study of immunobiology in vertebrates. Using laboratory Xenopus models, the proposed research will (1) comparatively profile the expression of intron-containing and intronless IFN subgroups during frog development and infection, (2) determine the functional capacity and evolutionary superiority of newly evolved intronless IFNs against the viral infection, (3) determine the dependence of amphibian IFN ligands on canonical IFN signaling pathways to induce effector genes and induce antiviral activity. These complimentary contributions will functionally characterize the IFN complex in amphibians, and ultimately fill a knowledge gap in IFN evolution. In addition, the proposed research will integrate collaborative efforts of the PI/Co-PIs at Tennessee State University (TSU), Vanderbilt University, and the University of Rochester to accomplish the objectives. It will train HBCU research personnel at two prominent research institutes and enhance research excellence and broaden STEM education at the minority-serving institution.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.