The role of BRG1 as a mediator of T-bet activity in lung-resident CD8+ T cell memory formation

BRG1 作为 T-bet 活性介质在肺驻留 CD8 T 细胞记忆形成中的作用

• 批准号: 10528432
• 负责人: Bryan McDonald
• 金额: $ 0.97万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528432
• 关键词: ATP phosphohydrolase; Antibodies; Antibody Formation; Antibody Response; Antibody-mediated protection; Antigens; Binding; Binding Sites; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Catalytic Domain; Cell Differentiation process; Cell Lineage; Cells; Cellular Immunity; Cessation of life; Chromatin; Chromatin Remodeling Factor; Clinical; Complex; Data; Development; Elderly; Enhancers; Epigenetic Process; Epitopes; Event; Exposure to; Gene Expression Profile; Generations; Genetic Transcription; Home; Hospitalization; Immune Evasion; Immunity; Immunize; Immunologic Memory; Individual; Influenza; Influenza A virus; Instruction; Knock-out; Lung; Maintenance; Mediator of activation protein; Membrane Glycoproteins; Memory; Mentorship; Molecular; Morbidity - disease rate; Mutation; Pattern; Play; Process; Regulatory Element; Research; Research Training; Residual state; Respiratory Tract Infections; Role; SMARCA4 gene; Scientist; Shapes; Signal Transduction; Specific qualifier value; Structure of parenchyma of lung; Sucrose; Surface; T memory cell; T-Lymphocyte; T-bet protein; Time; Tissues; To specify; Training; Vaccinated; Vaccines; Viral; Vulnerable Populations; Writing; analog; career; chromatin remodeling; design; flu; imprint; in vivo; influenza infection; influenza virus strain; influenza virus vaccine; insight; mortality; neutralizing antibody; overexpression; pathogen; rational design; respiratory pathogen; response; seasonal influenza; secondary infection; skill acquisition; statistics; technique development; thymocyte; tool; transcription factor; universal influenza vaccine; vaccine failure

Project Summary/Abstract Respiratory infections account for millions of hospitalizations and deaths each year globally. Notably, seasonal Influenza virus infections accounts for a significant fraction of these statistics, and attempts to vaccinate against these strains have mixed efficacy. Current strategies to immunize against influenza involve eliciting antibody responses against surface glycoproteins, but the high mutation rate of influenza allows for immune evasion against antibodies. Therefore, the design and development of influenza vaccines that provide long-lived cellular immunological memory and offers broad protection represents a major unmet clinical need. To this end, a vaccine that elicits memory CD8+ T cells, which recognize viral epitopes that are conserved across diverse flu strains, may be necessary for optimal protection. However, the cell-intrinsic molecular events involved in the formation of memory CD8+ T cells in the lung are poorly characterized. Additionally, it has been shown that lung tissue immunity wanes over time, resulting in a narrow window of protection against secondary infection. This proposal seeks to investigate how modulation of chromatin states influences the differentiation of lung resident memory (TRM) cells that are protective against influenza infection, with the hypothesis that the lineage-defining transcription factors T-bet and EOMES tunes the activity of the SWI/SNF chromatin remodeling complex to imprint chromatin states that promote TRM versus circulating memory (TCIRCM) cell fates. Three specific aims are proposed to interrogate this hypothesis. The first aim will define the T-bet and EOMES-bound regulatory elements that are permissive and/or instructive for lung TRM and TCIRCM cell differentiation. The second aim seeks to define chromatin states in TCIRCM and TRM cells that are dependent on BRG1, a core ATPase subunit of the SWI/SNF chromatin remodeling complex. Finally, the third aim will evaluate the importance of BRG1 in establishing chromatin states that promoting or suppressing lung TRM formation in vivo. In summary, this proposal seeks to provide insight into the molecular machinery that control the formation of lung TRM formation after flu infection. Understanding the mechanisms governing this process will enhance our capacity to induce long-lived protective cellular immunity in a vaccine setting against respiratory infections. This application details the applicant’s training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of academic research as an independent scientist.

项目摘要/摘要 呼吸道感染每年在全球占数百万个住院和死亡。值得注意的是，季节性 流感病毒感染占了这些统计数据的很大一部分，并试图接种疫苗接种 这些菌株具有混合效率。当前免疫影响影响力的策略涉及引起抗体 针对表面糖蛋白的反应，但是高影响力的高突变率可以免疫进化 反对抗体。因此，提供长寿细胞的影响力疫苗的设计和开发 免疫记忆并提供广泛的保护代表了主要未满足的临床需求。为此， 引起记忆CD8+ T细胞的疫苗，该疫苗识别在潜水员流感中保守的病毒表位 应变，可能是最佳保护所必需的。但是，与 肺中记忆CD8+ T细胞的形成的特征很差。此外，已经表明肺 随着时间的推移，组织免疫力会逐渐减弱，从而导致防止继发感染的狭窄窗口。这 提案旨在研究染色质状态的调节如何影响肺居民的分化 被保护免受影响力感染的记忆（TRM）细胞，并假设谱系定义 转录因子T-bet和Eomes调谐SWI/SNF染色质重塑复合物的活性 烙印染色质指出，促进TRM与循环记忆（TCIRCM）细胞命运。三个具体目标是 提议审问这一假设。第一个目标将定义T-BET和EOMES结合的调节 允许和/或具有肺部TRM和TCIRCM细胞分化的元素。第二个目标寻求 为了定义依赖于BRG1的TCIRCM和TRM细胞中的染色质状态，该状态是BRG1的核心ATPase亚基 SWI/SNF染色质重塑复合物。最后，第三个目标将评估BRG1在 建立染色质指出，体内促进或抑制肺TRM形成。总而言之，该提议 试图提供有关控制流感后肺TRM形成的分子机械的见解 感染。了解管理这一过程的机制将增强我们诱导长寿的能力 防止呼吸道感染的疫苗环境中的保护性细胞免疫。此应用程序详细介绍了 申请人的培训计划，包括研究指导，高级课程，新技术培训以及 发展科学专业，写作和数据介绍方面的技能。研究和培训 在本申请中概述的申请将为购买从事学术研究的职业的申请做好准备 独立科学家。