Lung-resident memory B cell development and function following influenza virus infection

流感病毒感染后肺驻留记忆 B 细胞的发育和功能

• 批准号: 10021844
• 负责人: BRIAN LAIDLAW
• 金额: $ 16.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021844
• 关键词: Acute respiratory infection; Antibodies; B-Cell Development; B-Lymphocytes; Blood Circulation; Cell Maintenance; Cells; Cellular Immunology; Cellular biology; Cessation of life; Collaborations; Development; Disease; Effectiveness; Foundations; Frequencies; Future; Glean; Goals; Homo; Hour; Immunity; Immunoglobulin-Secreting Cells; Immunologic Memory; Immunology; Infection; Influenza; Institutes; Knowledge; Laboratories; Leadership; Lung; Maintenance; Mediating; Medical; Memory B-Lymphocyte; Mentorship; Microbiology; Morbidity - disease rate; Pathology; Population; Positioning Attribute; Postdoctoral Fellow; Process; Publishing; Research; Research Personnel; Research Project Grants; Research Proposals; Resource Development; Seeds; Signal Transduction; Source; Structure of germinal center of lymph node; Time; Tissues; Training; Transcriptional Regulation; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Virus Diseases; Work; burden of illness; career development; cell motility; cross reactivity; design; draining lymph node; experience; flu; improved; influenza virus vaccine; influenzavirus; insight; lymphoid structures; migration; mortality; mouse model; precursor cell; prevent; professor; programs; receptor; residence; response; seasonal influenza; skills; tenure track; tool; trafficking; universal influenza vaccine; vaccine efficacy

Project Summary/Abstract: Candidate/Career Development: This proposal describes a 2-year research program in which the applicant, Dr. Brian Laidlaw, will establish himself as an independent investigator and work towards submitting a competitive application for regular research grant support. Dr. Laidlaw is currently a postdoctoral fellow in the laboratory of Dr. Jason Cyster, a Professor in the Department of Microbiology and Immunology at UCSF and an Investigator of the Howard Hughes Medical Institute. Dr. Cyster has immense experience preparing trainees for positions as independent investigators and is fully committed to providing Dr. Laidlaw with the support needed to successfully transition into a tenure-track position. Dr. Laidlaw will also utilize the extensive career development resources offered at UCSF, including a 16-hour course on Scientific Leadership and Laboratory Management, to strengthen his training in the skills required to successfully manage a research group. Dr. Laidlaw has established a mentorship committee and external collaborations to provide additional guidance on the described project and transition towards independence. In published work, Dr. Laidlaw characterized a population of memory B cell precursor cells residing within the germinal center following viral infection. He currently is using insight gleaned from that study to better understand the transcriptional regulation of memory B cell development and the influence of cell positioning in this process. Dr. Laidlaw will continue to explore the signals regulating memory B cell development as an independent investigator with the long-term goal of leveraging this knowledge in the design of vaccines better able to elicit a protective memory B cell response. Research Proposal: Influenza is an acute respiratory infection that is responsible for up to 650,000 deaths and 3-5 million cases of severe illness worldwide each year. While vaccination can prevent disease, seasonal flu vaccine efficacy ranges from 10-60% resulting in an urgent need to design broadly protective influenza vaccines. Memory B cells in the lungs can provide protection against influenza challenge, with this population possessing an elevated frequency of cross-reactive B cells capable of mediating heterosubtypic protection. This proposal seeks to investigate the processes regulating the development, maintenance, and reactivation of influenza-specific lung-resident memory B cells. This goal will be accomplished in two specific aims: 1) Investigate the mechanisms underlying B cell migration to and maintenance within the lungs and; 2) Explore the requirements for memory B cell reactivation within the lungs and their contribution to long- term protective immunity. The proposed research will significantly increase understanding of how lung-resident memory B cells develop and function with the long-term goal being to harness this knowledge to design vaccines better able to elicit these cells. This work will provide a foundation for future R01 applications centered on the contribution of resident memory B cells to protective immunity in settings of disease.

项目摘要/摘要： 候选人/职业发展：该提案描述了一项为期两年的研究计划，申请人，该计划， 布莱恩·莱德劳（Brian Laidlaw）博士将建立自己为独立调查员，并致力于提交 定期研究赠款支持的竞争申请。 Laidlaw博士目前是博士后研究员 UCSF微生物学和免疫学系教授Jason Cyster博士的实验室 霍华德·休斯医学院的调查员。 Cyster博士在准备学员方面拥有丰富的经验 作为独立调查员的职位，并完全致力于向Laidlaw博士提供支持 需要成功过渡到终身轨道。 Laidlaw博士还将利用广泛的职业 UCSF提供的发展资源，包括科学领导力和实验室的16小时课程 管理层，加强他在成功管理研究小组所需的技能方面的培训。博士 莱德劳（Laidlaw）成立了指导委员会和外部合作，以提供有关的其他指导 所描述的项目和向独立的过渡。 Laidlaw博士在出版的工作中表征了 病毒感染后，存储B细胞前体细胞的种群位于生发中心内。他 目前正在使用该研究中收集的洞察力来更好地了解记忆的转录调节 B细胞发育和细胞定位在此过程中的影响。 Laidlaw博士将继续探索 信号调节记忆B细胞发展为独立研究者，其长期目标的 利用这种知识在疫苗的设计中可以更好地引起保护性记忆B细胞反应。 研究建议：流感是一种急性呼吸道感染，可导致多达65万人死亡 以及全球3-5万例严重疾病。虽然疫苗接种可以预防疾病，但季节性 流感疫苗疗效的范围为10-60％，导致迫切需要设计广泛的保护性流感 疫苗。肺中的记忆B细胞可以提供防止流感挑战的保护 具有能够介导杂型保护的交叉反应性B细胞的频率升高。 该建议旨在调查规范开发，维护和 流感特异性肺部记忆B细胞的重新激活。这个目标将在两个中实现 具体目的：1）研究B细胞迁移到肺部的基础机制 和; 2）探索对肺部内存B细胞重新激活的要求及其对长期的贡献 术语保护性免疫。拟议的研究将大大提高人们对肺部居民的理解 记忆B细胞的发展和运作，其长期目标是利用这些知识设计 疫苗能够更好地引起这些细胞。这项工作将为未来的R01应用程序提供基础 集中在居民记忆B细胞对疾病环境中保护性免疫的贡献。