Discovery of New Innate Immune Pathways in Viral Recognition

病毒识别中新先天免疫途径的发现

基本信息

批准号：
8653231
负责人：
Jenny P Ting
金额：
$ 316.37万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8653231
关键词：
Affect Agonist Antiviral Response Attention Binding Biochemical Categories Cells DNA DNA Damage DNA Viruses Data Development Event Family Family Picornaviridae Fostering Goals Head Hepatitis A Virus Herpesviridae Human Human Herpesvirus 6 Human Herpesvirus 8 Human Virus Immune Immune response Immunity Infection Interferons International Investigation Leucine-Rich Repeat Ligand Binding Ligands Modification Molecular National Institute of Allergy and Infectious Disease Natural Immunity Nucleic Acid Binding Nucleic Acids Pathway interactions Pattern Pattern recognition receptor Play Proteins Proteome Proteomics Public Health Publishing RNA RNA Viruses Reporting Research Role Seminal Services Shapes Signal Pathway Signaling Protein Site Technology Testing Toll-like receptors Vaccines Vesicle Viral Virus Virus Diseases Virus Receptors Work adaptive immunity cell type combat economic impact long term memory microorganism interaction multidisciplinary novel nucleotide receptor pathogen programs protein purification public health relevance receptor receptor binding response sensor trafficking viral DNA

项目摘要

DESCRIPTION (as provided by applicant): A major conceptual advance in innate immunity is the discovery of Pathogen Recognition Receptors (PRR), which profoundly shape adaptive immunity to affect host response to pathogens. Major PRRs crucial for innate immunity against viral pathogens include toll-like receptors and RIG-I like receptors, while the role for NLR (nucleotide-binding leucine rich repeat containing, or NOD-like receptor) family in viral infection is just emerging. In this Program, we will focus on the revelation of novel nucleic acid sensing pathways relevant to multiple NIAID priority pathogens. The Program is comprised of three Projects, each led by an international leader in his/her field. The Program will be performed in a highly collaborative fashion with two Cores which will provide cutting edge proteomics and protein purification capabilities, headed by directors who have contributed seminal work in the field of PRRs. The overarching goals are: * To investigate the role of novel PRRs as receptors of viral nucleic acid which affect subsequent innate immune responses to NIAID high priority viral pathogens in human. * To apply cutting edge quantitative proteomic approaches for the identification of novel paradigm-shifting pathways of pathogen sensing. * To contrast and compare role of PRRs across diverse NIAID high priority human viruses. * To reveal cross-talk between multiple PRRs in host response to NIAID priority human viruses * To investigate intracellular trafficking of viral ligands to sites of recognition by PRRs. * To capitalize on unique biochemical capabilities that are technically challenging to quantify the ligand-binding functions of PRRs. * To maximize opportunities for validating experimental findings with primary human materials. These goals are highly response to the RFA-AI-12-048 and are in precise concordance with the stated purpose of the RFA that "emphasis of research proposed in response to this FOA should be in defining novel cellular and molecular immune mechanisms involved in immunity to virus infection". It is also responsive because the pathways explored are broadly relevant to multiple high priority pathogens and will be studied in the context of five high priority RNA and DNA viruses. Finally, the proposed work is responsive to the purpose of the RFA because it specifically expands our understanding of novel PRR interaction with viruses and the accompanied changes in signaling pathways by profiling proteomic modifications in human innate immune cells caused by NIAID priority viral pathogens.

描述（如申请人提供）：先天免疫的主要概念进步是发现病原体识别受体（PRR），它深刻地塑造了适应性免疫以影响宿主对病原体的反应。对病毒病原体的先天免疫至关重要的主要PRR包括Toll样受体和类似RIG-I的受体，而NLR的作用（核苷酸结合的亮氨酸含有富含亮氨酸的重复含有含量含有含有木质的亮氨酸或nod样受体）在病毒感染中只是出现。在该程序中，我们将重点关注与多个NIAID优先病原体有关的新型核酸传感途径的启示。该计划由三个项目组成，每个项目都由其领域的国际领导人领导。该程序将以高度协作的方式与两个核心一起执行，这些核心将提供最先进的蛋白质组学和蛋白质纯化功能，该功能由在PRR领域贡献精确工作的导演领导。总体目标是： *研究新的PRR作为病毒核酸的受体的作用，影响了人类对NIAID高优先病毒病原体的随后的先天免疫反应。 *用于应用尖端定量蛋白质组学方法，以鉴定病原体传感的新型范式转移途径。 *对比和比较PRR在各种高优先级人类病毒中的作用。 *在宿主对NIAID优先人类病毒的宿主反应中，多个PRR之间的串扰 *研究病毒配体的细胞内贩运对PRR的识别部位。 *利用独特的生化能力，在技术上具有挑战性，可以量化PRR的配体结合功能。 *最大限度地利用原始材料验证实验发现的机会。这些目标是对RFA-AI-12-048的高度响应，并且与RFA的既定目的相一致，即“针对该FOA提出的研究的重点应该在于定义针对病毒感染免疫的新型细胞和分子免疫机制定义新型细胞和分子免疫机制”。它也很灵敏，因为所探索的途径与多个高优先病原体广泛相关，并且将在五个高优先级RNA和DNA病毒的背景下进行研究。最后，提出的工作对RFA的目的有响应，因为它专门扩展了我们对新型PRR与病毒相互作用的理解，以及通过分析由NIAID优先病毒病毒病原体引起的人类先天免疫细胞中蛋白质组学修饰的信号传导途径的随附变化。