Regulatory genomics of T cells in mouse and human

小鼠和人类 T 细胞的调控基因组学

• 批准号: 10507476
• 负责人: Yury Pritykin
• 金额: $ 47.67万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507476
• 关键词: ATAC-seq; Adaptive Immune System; Address; Age; Architecture; Autoantigens; Autoimmunity; Bacterial Infections; Biological; Biological Assay; CD8-Positive T-Lymphocytes; Cell Communication; Cell Lineage; Cell physiology; Cells; Chromatin; Clinical; Collaborations; Communicable Diseases; Computational algorithm; Computer Analysis; Computer software; Computing Methodologies; Data; Databases; Disease; Environmental Risk Factor; FOXP3 gene; Future; Gender; Gene Expression; Generations; Genomics; Genotype; Goals; Heterogeneity; Hi-C; Human; Hypersensitivity; Immunity; Immunologic Deficiency Syndromes; Immunologics; Life Style; Lymphocytic choriomeningitis virus; Machine Learning; Maintenance; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Analysis; Mus; Noise; Population; Process; Property; Recording of previous events; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Resolution; Role; Stimulus; Sum; System; T cell regulation; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; Transcriptional Regulation; Validation; Virus Diseases; adaptive immunity; cell type; cohort; comparative; data exploration; data resource; epigenetic regulation; genomic data; humanized mouse; improved; innovation; machine learning method; microbiota; mouse model; multidimensional data; multiple omics; novel therapeutics; pathogen; prevent; progenitor; programs; research and development; response; supervised learning; transcription factor; transcriptome sequencing; translational applications; translational barrier; tumor

Project Summary/Abstract T cells coordinate systemic immunity and are essential for defense against viral and bacterial infections and tu- mors. The long-term goal of our research program is to employ innovative experimental genomics to build multi- dimensional data resources and develop new computational methods that we will use to obtain a comprehensive understanding at a molecular level of T cell activation and differentiation in response to various stimuli. We will address specific problems about T cell commitment to functional fates across contexts, regulatory mechanisms of these processes and their underlying transcription factors. Unprecedented resolution and statistical power will allow us to study similarities and differences of these mechanisms between T cell lineages and subpopulations, and generalizability of these observations from mouse to human. This goal will be achieved by executing three projects. We will study regulation of T cell activation and functional commitment in lymphocytic choriomeningi- tis virus (LCMV) infection model with a focus on the progenitor TCF1+ T cells (Project 1), transcriptional and epigenetic regulation and higher order chromatin organization in Treg cells (Project 2). Finally, we will build a database, methods, software and interfaces for comparative analysis of regulatory genomics data across mouse models and humans, allowing many fundamental and translational applications (Project 3). These studies will lead to future research and development of new therapeutic transcription factor and other targets and modulation strategies in diseases of dysregulated T cell immunity. Our data resources and methods will enable systematic data exploration, generation and validation of new specific hypotheses about molecular mechanisms of T cell function, and will provide a platform for mapping and analyzing new T cell data from new systems that we and others will generate in the future.

项目总结/摘要 T细胞协调全身免疫，对于防御病毒和细菌感染以及免疫至关重要。 mors。我们的研究计划的长期目标是采用创新的实验基因组学，以建立多 三维数据资源，并开发新的计算方法，我们将使用这些方法来获得全面的 在分子水平上理解T细胞对各种刺激的活化和分化。我们将 解决关于T细胞在不同环境、调节机制中对功能命运的承诺的具体问题 这些过程及其潜在的转录因子。前所未有的分辨率和统计能力将 使我们能够研究T细胞谱系和亚群之间这些机制的相似性和差异， 以及这些观察结果从小鼠到人类的普遍性。这一目标将通过执行三个 项目我们将研究淋巴细胞脉络膜中T细胞活化和功能承诺的调节， tis病毒（LCMV）感染模型，重点是祖TCF 1 + T细胞（项目1），转录和 Treg细胞中的表观遗传调控和高级染色质组织（项目2）。最后，我们将建立一个 用于跨小鼠的调节基因组学数据的比较分析的数据库、方法、软件和界面 模型和人类，允许许多基础和翻译应用程序（项目3）。这些研究将 导致未来研究和开发新治疗性转录因子和其它靶点和调节 T细胞免疫失调疾病的治疗策略。我们的数据资源和方法将使系统 数据探索，产生和验证关于T细胞分子机制的新的具体假设 功能，并将提供一个平台，用于映射和分析来自新系统的新T细胞数据， 其他人将在未来产生。