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

项目概要/摘要： 候选人/职业发展：本提案描述了一个为期2年的研究计划，其中申请人， 博士布赖恩莱德劳，将建立自己作为一个独立的调查员，并致力于提交一份 竞争性申请定期研究资助。Laidlaw博士目前是一名博士后研究员， Jason Cyster博士的实验室，加州大学旧金山分校微生物学和免疫学系教授， 霍华德休斯医学研究所的研究员Cyster博士在培训学员方面有丰富的经验 作为独立调查员的职位，并完全致力于为莱德劳博士提供支持， 需要成功过渡到终身教职。莱德劳博士还将利用他在 加州大学旧金山分校提供的发展资源，包括16小时的科学领导和实验室课程 管理，以加强他的培训所需的技能，成功地管理一个研究小组。博士 Laidlaw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， 所述项目和向独立过渡。在已发表的著作中，莱德劳博士描述了 病毒感染后，记忆B细胞前体细胞群驻留在生发中心内。他 目前正在使用从该研究中收集的见解，以更好地了解记忆的转录调节 B细胞发育以及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细胞的发展，作为一个独立的研究者，长期目标是 在疫苗设计中利用这些知识，更好地引发保护性记忆B细胞应答。 研究建议：流感是一种急性呼吸道感染，导致多达65万人死亡 全世界每年有300万到500万例重症病例。虽然接种疫苗可以预防疾病，但季节性 流感疫苗的效力范围为10-60%，因此迫切需要设计广泛的保护性流感疫苗。 疫苗。肺中的记忆B细胞可以提供针对流感攻击的保护， 具有能够介导异亚型保护的交叉反应性B细胞的频率升高。 该提案旨在调查管理开发，维护和维护的过程， 流感特异性肺驻留记忆B细胞的再激活。这一目标将在两个 具体目的：1）研究B细胞迁移到肺内并在肺内维持的机制 和; 2）探索肺内记忆B细胞再活化的要求及其对长期- 保护性免疫。这项拟议中的研究将大大增加对肺部居民如何 记忆B细胞的发展和功能的长期目标是利用这些知识来设计 疫苗能更好地激发这些细胞。这项工作将为R 01的未来应用奠定基础 集中于常驻记忆B细胞在疾病环境中对保护性免疫的贡献。

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.