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

项目摘要/摘要： 候选人/职业发展：这份建议书描述了一项为期两年的研究计划，在该计划中，申请者 布莱恩·莱德洛博士将确立自己作为独立调查员的地位，并努力提交一份 竞相申请定期研究资助。莱德洛博士目前是 加州大学旧金山分校微生物学和免疫学系教授Jason Cyster博士的实验室 霍华德·休斯医学研究所的研究员。赛斯特博士在培训学员方面有丰富的经验 作为独立调查人员的职位，并完全致力于为莱德洛博士提供支持 需要成功地过渡到终身教职的职位。莱德洛博士还将利用广泛的职业生涯 加州大学旧金山分校提供的发展资源，包括16小时的科学领导力和实验室课程 加强他在成功管理研究小组所需技能方面的培训。Dr。 莱德洛已经建立了一个指导委员会和外部合作，以提供更多的指导 所述项目和向独立的过渡。在发表的研究中，莱德洛博士描述了一种 病毒感染后，位于生发中心内的记忆B细胞前体细胞群。他 目前正在使用从这项研究中收集的洞察力来更好地理解记忆的转录调节 B细胞发育及细胞定位在这一过程中的影响。莱德洛博士将继续探索 作为一个独立的研究人员，调节记忆B细胞发育的信号，其长期目标是 在疫苗设计中利用这一知识，能够更好地诱导保护性记忆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 全世界每年有300-500万例严重疾病。虽然接种疫苗可以预防疾病，但季节性的 流感疫苗的有效率在10%-60%之间，因此迫切需要设计具有广泛保护性的流感疫苗 疫苗。肺部的记忆B细胞可以提供抵御流感挑战的保护，在这一人群中 具有高频率的交叉反应性B细胞，能够介导异型保护。 本提案旨在调查规范开发、维护和 流感特异性肺驻留记忆B细胞的重新激活。这一目标将在两年内实现 具体目标：1)研究B细胞向肺内迁移和维持的机制 以及2)探讨记忆B细胞在肺内重新激活的要求及其对长效应激的作用。 长期保护豁免权。这项拟议中的研究将显著增加对肺部居住者如何 记忆B细胞的发育和功能的长期目标是利用这一知识来设计 疫苗能够更好地诱导这些细胞。这项工作将为未来R01的应用奠定基础 以常驻记忆B细胞在疾病背景下对保护性免疫的贡献为中心。

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.