Project 3 - Zuniga

项目3-祖尼加

• 批准号: 10453793
• 负责人: Elina I Zuniga
• 金额: $ 45.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-17 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453793
• 关键词: ATAC-seq; Allergic Disease; Arenavirus; Autoimmunity; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cartoons; Cells; Chronic; Communicable Diseases; Computer Analysis; Data; Development; Disease; Down-Regulation; Epigenetic Process; Exhibits; Family member; Foundations; Genes; Genetic Transcription; Growth; HIV; Hepatitis B Virus; Hepatitis C virus; Heterogeneity; Host Defense; Hypersensitivity; Immune; Immunotherapy; Infection; Inflammatory; JUN gene; Knowledge; Laboratories; Lead; Location; Lymphocyte; Lymphocytic choriomeningitis virus; MADH4 gene; MAPK9 gene; Malignant Neoplasms; Mediating; Memory; Methodology; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Pathogenicity; Play; Population; Predisposition; Production; Proteins; Regulation; Reporting; Research; Role; Secondary to; Signal Transduction; Small Intestines; T cell differentiation; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Tissues; Transcription Repressor; Transforming Growth Factor beta; Tumor-Infiltrating Lymphocytes; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Work; acute infection; antagonist; base; burden of illness; chronic infection; combat; cytokine; exhaust; exhaustion; immunoregulation; in vivo; innovation; mouse model; novel; novel strategies; pathogen; prevent; receptor; response; screening; secondary infection; single-cell RNA sequencing; small hairpin RNA; transcription factor; tumor

SUMMARY-PROJECT 3-ZUNIGA: Tissue-resident memory (Trm) CD8+ T cells are a distinct subset of memory cells that provide an essential frontline of defense against microbes at mucosal barriers and non-barrier tissues. Although Trm are now recognized to play critical roles in host defense against acute infection, their function and molecular regulation during persistent infections have been largely unexplored. This knowledge gap is fundamentally important given that infection persists primarily in non-lymphoid tissues following chronic infection. As persistent infections such as HIV, HCV and HBV are responsible for tremendous disease burden worldwide, understanding immune regulation in non-lymphoid tissues will inform novel strategies to harness Trm against chronic infections and tumors. We propose innovative approaches to elucidate new mechanisms that specifically promote Trm exhaustion, the progressive loss of effector functions, leading to persistent pathogen in tissues and enhancing susceptibility to secondary infections. These studies will likely redefine current models of CD8+ T cell differentiation, fate and function during persistent viral infection as the current understanding of T cell exhaustion is almost exclusively based on studying circulating lymphocyte populations. Specifically, we will: (1) Decipher the unique molecular regulation and heterogeneity of exhausted Trm using cutting-edge single-cell RNA-seq and small-cell-number epigenetic methodologies combined with novel integrative computational analyses. Novel regulators of exhausted Trm identified in these studies will be tested with high-throughput functional in vivo shRNA screening. (2) Elucidate the mechanisms by which T-box transcription factors, T-bet and Eomes, and the transcriptional repressor Ezh2 differentially operate to control Trm differentiation in acute and chronic infection. (3) Investigate how non-canonical TGFβ signaling components regulate Trm development and exhaustion. Our studies will leverage the data and expertise represented in the other Project and Core laboratories to define the functional and molecular determinants of Trm differentiation, retention, and exhaustion, providing the foundation with which to effectively manipulate this CD8+ T cell subset to combat chronic infectious diseases and cancer where tumor infiltrating lymphocytes undergo exhaustion. As LCMV is a prototypic member of the family arenaviridae, our work will also help explain T cell suppression caused by hemorrhagic fever arenaviruses. Moreover, we anticipate that the basic knowledge on Trm regulation that will be gathered from our studies will have broad implications for other immune-related diseases in which Trm have been shown to play a pathogenic role, such as allergy and autoimmunity.

项目3-ZUNIGA概述： 组织驻留记忆（Tissue-resident memory，Trm）CD 8 + T细胞是记忆细胞的一个独特亚群，它提供了一种重要的免疫调节功能。 粘膜屏障和非屏障组织的微生物防御前线。虽然现在Trm 被认为在宿主防御急性感染中起关键作用，它们的功能和分子调控 在持续性感染中的作用在很大程度上尚未被探索。这种知识差距至关重要 因为慢性感染后感染主要在非淋巴组织中持续存在。为持久性 诸如HIV、HCV和HBV感染是造成全世界巨大疾病负担的原因， 了解非淋巴组织中的免疫调节将为利用Trm对抗 慢性感染和肿瘤。 我们提出了创新的方法来阐明新的机制，特别是促进Trm耗尽， 效应子功能的逐渐丧失，导致组织中持续存在病原体并增强易感性 继发感染。这些研究可能会重新定义目前的CD 8 + T细胞分化，命运和分化的模型。 由于目前对T细胞耗竭的理解几乎完全是 基于对循环淋巴细胞群的研究。具体而言，我们将：（1）破译独特的分子 使用尖端的单细胞RNA-seq和小细胞数的Trm耗尽的调节和异质性 表观遗传学方法结合新的综合计算分析。新型调节剂 在这些研究中鉴定的耗尽的Trm将用高通量功能性体内shRNA进行测试 筛选(2)阐明了T-box转录因子T-bet和Eomes以及T-bet和Eomes的作用机制。 转录抑制因子Ezh 2在急性和慢性感染中不同地控制Trm分化。 (3)研究非经典TGFβ信号传导组分如何调节Trm的发育和耗竭。我们 研究将利用其他项目和核心实验室的数据和专业知识， Trm分化、保留和耗竭的功能和分子决定因素，提供了 有效操纵这种CD 8 + T细胞亚群以对抗慢性感染性疾病的基础 和肿瘤浸润淋巴细胞耗尽的癌症。由于LCMV是 我们的工作也将有助于解释出血热引起的T细胞抑制 沙粒病毒此外，我们预计，将从以下方面收集有关Trm监管的基本知识： 我们的研究将对其他免疫相关疾病产生广泛的影响， 发挥致病作用，如过敏和自身免疫。