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

项目摘要/摘要 全球每年有数百万人因呼吸道感染住院和死亡。值得注意的是，季节性的 流感病毒感染占这些统计数据的很大一部分，并试图接种疫苗以预防 这些菌株的疗效参差不齐。目前针对流感的免疫策略包括诱导抗体 对表面糖蛋白的反应，但流感的高突变率允许免疫逃避 对抗抗体。因此，设计和开发提供长寿细胞的流感疫苗 免疫记忆和提供广泛的保护代表着一个主要的未得到满足的临床需求。为此，一个 一种激发记忆CD8+T细胞的疫苗，这种细胞识别在不同流感中保守的病毒表位 菌株，可能是最佳保护所必需的。然而，细胞内固有的分子事件参与了 肺内记忆性CD8+T细胞的形成特征较差。此外，有研究表明，肺 组织免疫力随着时间的推移而减弱，导致对继发感染的保护窗口很窄。这 该提案旨在调查染色质状态的调节如何影响肺居民的分化 记忆(TRM)细胞对流感感染具有保护作用，假设谱系定义 转录因子T-bet和eome调节SWI/SNF染色质重塑复合体的活性以 印迹染色质状态促进TRM与循环记忆(TCIRCM)细胞命运。三个具体目标是 提出了对这一假说的质疑。第一个目标将定义T-bet和受Eome约束的监管 允许和/或指导肺TRM和TCIRCM细胞分化的元素。第二个目标是寻求 为了定义TCIRCM和TRM细胞中依赖BRG1的染色质状态，BRG1是ATPase的核心亚单位 SWI/SNF染色质重塑复合体。最后，第三个目标将评估BRG1在 建立染色质说明在体内促进或抑制肺TRM的形成。总而言之，这项提案 旨在提供对控制流感后肺TRM形成的分子机制的洞察 感染。了解管理这一过程的机制将增强我们诱导长期生存的能力 预防呼吸道感染的疫苗设置中的保护性细胞免疫。此应用程序详细说明了 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 发展科学专业精神、写作和数据表达方面的技能。研究和培训 这份申请书中概述的内容将使申请者为从事学术研究做好准备 一个独立的科学家。

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.