Project 1 - Goldrath

项目1-戈德拉思

基本信息

批准号：
10214455
负责人：
Ananda W Goldrath
金额：
$ 50.02万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214455
关键词：
Acute Adopted Adoptive Transfer Affect Antigens Automobile Driving Blood Body Surface CD8-Positive T-Lymphocytes Cell Differentiation process Cell division Cells Cellular biology ChIP-seq Chronic Communicable Diseases Data Dependence Development E protein Effector Cell Enhancers Epigenetic Process Equilibrium Event Exhibits FOXO1A gene FOXO3A gene Gene Expression Gene Expression Profiling Generations Genes Genetic Transcription Genomics Goals Heterogeneity Homeostasis Hybrids ID2 gene Immune Immunologic Memory Impairment Individual Infection Inflammation Inhibitor of Differentiation Proteins Literature Lymphoid Tissue Maintenance Malignant Neoplasms Mediating Memory Messenger RNA Metabolic Pathway Modeling Molecular Neoplasm Metastasis Pathway interactions Phenotype Population Proteins Regulatory Element Reporter Role Sentinel T cell differentiation T memory cell T-Lymphocyte Testing Tissue Differentiation Tissues Transcription Repressor Vital capacity acute infection base cell fate specification chronic infection design first responder immunopathology improved in vivo inhibitor/antagonist intestinal epithelium novel vaccines programs recruit residence response screening single cell analysis single-cell RNA sequencing small hairpin RNA transcription factor tumor growth

项目摘要

SUMMARY-PROJECT 1-GOLDRATH: Long-lived memory cells provide protection from reinfection and can serve as endogenous defenders against tumor growth and metastases. Tissue-resident memory T cells provide essential sentinel protection at body surfaces such as the intestinal epithelium, and are now clearly understood to be among the key `first responders' in many infection settings. Although we know that resident-memory cells are an essential component of immune memory, little is known about the transcriptional pathways regulating their formation, survival and function. Improving our understanding of these topics will allow us to harness the immediate protective capacity of this vital memory T cell population and modulate their activity in the context of immunopathology, which is the overarching goal of the Program Project. Benefiting from the combined expertise in cutting-edge epigenetic and genomic analyses, CD8+ T cell biology, and chronic infection of the Program Project and Core Leaders, Project 1 will define the relationship of transcriptional programs driving unique memory states with a focus on resident versus circulating memory populations. The heterogeneity, gene-expression programs, functional activity and regulatory elements involved in resident- memory cell development will be studied to generate an integrated understanding of how transcriptional regulators such as Blimp1, Bcl6, T-bet, and E/Id proteins drive divergent differentiation programs in memory cell precursors to promote differentiation of distinct memory fates. To this end, specifically, we will: (1) Define the relationship of transcriptional programs driving unique memory states to understand how resident-memory T cell differentiation diverges from circulating memory T cell populations. Single-cell analysis of gene expression will be paired with high-throughput functional screening to assess the hybrid transcriptional network regulating the formation and homeostasis of Trm populations. (2) Decipher the contradictory dependence of Trm on the antagonistic transcriptional repressors, Blimp1 and Bcl6 in Trm differentiation and homeostasis. (3) Resolve the role of E protein transcription factors and their regulators in the transcriptional network governing the development, function and homeostasis of tissue-resident memory T cells in acute and chronic infectious settings. Our studies identifying key molecular determinants and transcriptional programs that control resident- memory T cell fate specification are critical to inform the rational design of the next generation of vaccines that will specifically aim to invoke tissue-resident memory cell-mediated protection from infectious diseases and malignancy. !

摘要-项目 1-GOLDRATH：长寿命的记忆细胞可防止再次感染，并可作为内源性防御者肿瘤生长和转移。组织驻留记忆 T 细胞为身体提供重要的哨兵保护肠上皮等表面，现在被清楚地理解为关键的“第一许多感染环境中的响应者。尽管我们知道常驻记忆细胞是必不可少的免疫记忆的组成部分，但人们对调节其形成的转录途径知之甚少，生存和功能。提高我们对这些主题的理解将使我们能够利用这一点的直接保护能力重要记忆 T 细胞群并在免疫病理学背景下调节其活性，这是该计划项目的总体目标。受益于尖端表观遗传学的综合专业知识和基因组分析、CD8+ T 细胞生物学以及项目项目和核心领导者的慢性感染，项目 1 将定义驱动独特记忆状态的转录程序的关系，重点是常驻记忆群体与循环记忆群体。居民参与的异质性、基因表达程序、功能活动和调控元件将研究记忆细胞的发育，以全面了解转录如何进行 Blimp1、Bcl6、T-bet 和 E/Id 蛋白等调节因子驱动记忆中的不同分化程序细胞前体促进不同记忆命运的分化。为此，具体而言，我们将： (1) 定义驱动独特记忆状态的转录程序的关系，以了解常驻记忆如何 T 细胞分化不同于循环记忆 T 细胞群。基因的单细胞分析表达将与高通量功能筛选相结合，以评估混合转录网络调节 Trm 群体的形成和稳态。 (2) 破译矛盾依赖关系 Trm 对 Trm 分化和稳态中拮抗转录抑制因子 Blimp1 和 Bcl6 的影响。 (3) 解析E蛋白转录因子及其调控因子在转录网络调控中的作用急性和慢性感染中组织驻留记忆 T 细胞的发育、功能和稳态设置。我们的研究确定了控制常驻的关键分子决定因素和转录程序记忆 T 细胞命运规范对于下一代疫苗的合理设计至关重要将特别旨在调用组织驻留记忆细胞介导的传染病保护，恶性肿瘤。！