Comparative functional genomics of innate immunity in deuterostomes

后口动物先天免疫的比较功能基因组学

• 批准号: 1755377
• 负责人: Kenneth Halanych
• 金额: $ 53.53万
• 依托单位: Auburn University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755377&HistoricalAwards=false
• 关键词: Comparative; functional; genomics; innate; immunity

Animals use an innate immune system to protect themselves from pathogens, such as viruses and bacteria. Receptors of the innate immune system that recognize such pathogens are important for starting the process of pathogen clearance, and are unchanged over an individual's lifetime. Moreover, several genes involved in innate immunity appear to be evolutionarily conserved across major animal groups. Researchers have little understanding of how innate mechanisms of immunity recognize and defend against the wide diversity of microbes and viruses encountered by different animals in different environments. To explore this question, as well as to more fully understand the genetic setting that led to the evolution of the adaptive immune system in vertebrates, researchers will explore the diversity and conservation of innate immune mechanisms across deuterostome animals (a group that includes acorn worms, sea stars, sea cucumbers, sea squirts, and vertebrates). To undertake this work, researchers will employ novel genomic data, develop bioinformatic tools, and use an experimental approach to understand which innate immune genes are activated, or repressed, when various antigens are presented to the study animal. Acorn worms, relatives of chordates for which little is known, will be a main focus of experimental work. Additionally, investigators will train undergraduate and graduate students drawn form diverse backgrounds. Workshops focused on elementary and middle schools students will transfer knowledge and excitement about biodiversity, genomic tools, and immunology.Pattern Recognition Receptor (PRR) pathways are part of an ancient innate immune defense system spanning Metazoa, and are known to react to conserved molecular motifs exhibited by common pathogens (e.g., viruses, bacteria, fungi). Pattern Recognition Receptor-facilitated defenses include pathways initiated by Toll-Like Receptors (TLR), RIG-I like Receptors, and NOD-like receptors. Unfortunately, the evolution of innate immune systems across invertebrates, including the ancestral state for deuterostomes, is unclear. Moreover, the breadth of TLR-facilitated ligand-specificity has been suggested to be fine-tuned to the niche an organism occupies, despite exhibiting evolutionary conservation across lineages and thus, evolutionary time. The functional novelty of Pattern Recognition Receptors, origins or associated pathways, and degree of evolutionary conservation are open questions. This study combines informatics and experimental tools to, 1) gain insight on the ancestral state of innate immunity in hemichordates, ambulacrarians, and ultimately deuterostomes, 2) further understand the setting of organismal pathogen-defense systems preceding the genesis of adaptive immunities, and 3) quantitatively assess variation and divergence of innate immunity elements over evolutionary time. Differential gene expression and in situ hybridization will be used in controlled settings to assess deployment and responsiveness of innate immunity pathways. Functional conservation will be assessed with experimental rescue of human TLR-/- cell lines with the corresponding hemichordate orthologs. The project will promote career development for a Beginning Investigator, graduate students, and undergraduates. A set of outreach workshops (with immunology, genomic and evolution themes) is specifically proposed that will reach K5-8 and their parents. This work seeks to support participation of under-represented groups and summer interns.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.

动物使用先天免疫系统来保护自己免受病原体的侵害，如病毒和细菌。识别这些病原体的先天免疫系统的受体对于启动病原体清除过程是重要的，并且在个体的一生中是不变的。此外，参与先天免疫的几个基因似乎在主要动物群体中进化保守。研究人员对先天免疫机制如何识别和防御不同动物在不同环境中遇到的各种微生物和病毒知之甚少。为了探索这个问题，以及更全面地了解导致脊椎动物适应性免疫系统进化的遗传背景，研究人员将探索后口动物（包括橡子蠕虫，海星，海参，海葵和脊椎动物）先天免疫机制的多样性和保护。为了开展这项工作，研究人员将采用新的基因组数据，开发生物信息学工具，并使用实验方法来了解当各种抗原呈现给研究动物时，哪些先天免疫基因被激活或抑制。橡子蠕虫，脊索动物的亲戚，其中知之甚少，将是实验工作的主要重点。此外，研究人员将培训来自不同背景的本科生和研究生。模式识别受体（PRR）途径是跨越后生动物的古老先天免疫防御系统的一部分，并且已知对常见病原体（例如，病毒、细菌、真菌）。模式识别受体促进的防御包括由Toll样受体（TLR）、RIG-I样受体和NOD样受体启动的途径。不幸的是，无脊椎动物先天免疫系统的进化，包括后口动物的祖先状态，尚不清楚。此外，TLR促进的配体特异性的宽度已被建议微调到一个生物体占据的生态位，尽管表现出跨谱系的进化保守性，因此，进化时间。模式识别受体的功能新奇、起源或相关途径以及进化保守程度是一个悬而未决的问题。这项研究结合了信息学和实验工具，1）深入了解半索动物，步肢动物和最终后口动物先天免疫的祖先状态，2）进一步了解适应性免疫发生之前生物体病原体防御系统的设置，3）定量评估先天免疫元素在进化过程中的变化和分歧。差异基因表达和原位杂交将在受控环境中用于评估先天免疫途径的部署和反应性。将通过用相应的半索酸直系同源物对人TLR-/-细胞系的实验拯救来评估功能保守性。该项目将促进职业发展的开始研究员，研究生和本科生。 专门提议举办一系列外展研讨会（以免疫学、基因组和进化为主题），以帮助K5-8及其父母。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。