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

项目总结/摘要 呼吸道感染每年导致全球数百万人住院和死亡。特别是季节性的 流感病毒感染占这些统计数据的很大一部分， 这些菌株具有混合的功效。目前针对流感的免疫策略包括引发抗体 针对表面糖蛋白的免疫应答，但流感的高突变率允许免疫逃避 对抗抗体。因此，提供长寿命细胞免疫的流感疫苗的设计和开发， 免疫记忆并提供广泛的保护代表了主要的未满足的临床需求。为此，A 疫苗，激发记忆CD 8 + T细胞，识别在不同流感病毒中保守的病毒表位， 菌株，可能是必要的最佳保护。然而，参与细胞内的分子事件， 记忆性CD 8 + T细胞在肺中的形成特征不明显。此外，已经表明肺 随着时间的推移，组织免疫力减弱，导致对继发感染的保护窗口变窄。这 一项提案旨在研究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EOMES调节SWI/SNF染色质重塑复合物的活性， 印记染色质状态促进TRM与循环记忆（TCIRCM）细胞命运。三个具体目标是 他试图质疑这个假设。第一个目标将定义T-bet和EOMES约束的监管 允许和/或指导肺TRM和TCIRCM细胞分化的元件。第二个目标是 为了确定TCIRCM和TRM细胞中依赖于BRG 1的染色质状态，BRG 1是TIRCM和TRM细胞的核心ATP酶亚基。 SWI/SNF染色质重塑复合物。最后，第三个目标将评估BRG 1在以下方面的重要性： 在体内建立促进或抑制肺TRM形成的染色质状态。总而言之，这一提议 旨在提供对流感后控制肺TRM形成的分子机制的深入了解 感染了解这一过程的机制将提高我们诱导长寿的能力。 在针对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、写作和数据呈现方面的技能。研究和培训 概述在此应用程序将准备申请人追求的职业生涯中进行学术研究， 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.