Project 1 - Goldrath

项目1-戈德拉思

• 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
• 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

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. !

项目1-戈德拉斯概述： 长寿记忆细胞提供保护，防止再感染，并可以作为内源性防御者， 肿瘤生长和转移。组织驻留记忆T细胞在身体中提供必要的哨兵保护 表面，如肠上皮，现在清楚地了解到，是关键的“第一次”， 在许多感染环境中的响应者。虽然我们知道，常驻记忆细胞是一个必不可少的 作为免疫记忆的组成部分，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种直接的保护能力， 重要的记忆T细胞群，并在免疫病理学的背景下调节它们的活性，这是 项目的总体目标。得益于尖端的表观遗传学 和基因组分析，CD 8 + T细胞生物学，以及计划项目和核心领导人的慢性感染， 项目1将定义驱动独特记忆状态的转录程序之间的关系，重点是 常驻内存与循环内存的对比 目前，研究人员对参与常驻基因表达的异质性、基因表达程序、功能活性和调控元件进行了综述。 记忆细胞的发展将被研究，以产生一个完整的理解如何转录 Blimp 1、Bcl 6、T-bet和E/Id蛋白等调节因子驱动记忆中的分化程序 细胞前体来促进不同记忆命运的分化。为此，我们将：（1）定义 转录程序驱动独特的记忆状态的关系，以了解如何居民记忆 T细胞分化与循环记忆T细胞群不同。基因的单细胞分析 表达将与高通量功能筛选配对，以评估杂交转录网络 调节Trm群体的形成和稳态。(2)解读的矛盾依赖 Trm对Trm分化和稳态中拮抗性转录抑制因子Blimp 1和Bcl 6的影响。（三） 解析E蛋白转录因子及其调控因子在调控转录网络中的作用 组织驻留记忆T细胞在急、慢性感染中的发育、功能和稳态 设置.我们的研究确定了关键的分子决定因素和转录程序，控制居民- 记忆性T细胞命运特化对于告知下一代疫苗的合理设计至关重要， 将特别致力于激发组织驻留记忆细胞介导的对感染性疾病的保护， 恶性肿瘤 !