Integrating T cell receptor features with gene expression profiles to define T cell specificity and differentiation

将 T 细胞受体特征与基因表达谱整合以定义 T 细胞特异性和分化

• 批准号: 10569090
• 负责人: Philip Bradley
• 金额: $ 22.37万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569090
• 关键词: Algorithms; Antigen Receptors; Atlases; Autoimmune Diseases; COVID-19 pandemic; Catalogs; Cell physiology; Cells; Clinical; Collaborations; Consensus; Data; Data Set; Databases; Development; Disease; Epitopes; Gene Expression; Gene Expression Profile; Goals; Graph; Human; Immune; Immune response; Immunologics; Immunologist; Individual; Infectious Diseases Research; Link; Literature; Malignant Neoplasms; Maps; Mediating; Meta-Analysis; Metadata; Participant; Phenotype; Population; Process; Recurrence; Research Personnel; Resolution; Resources; Running; Specificity; Standardization; Surface; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Technology; Tissues; Work; analytical method; analytical tool; data cleaning; data standards; diverse data; improved; infectious disease treatment; innovation; insight; interest; multimodality; novel; novel strategies; pathogen; receptor expression; response; secondary analysis; single cell analysis; tool

ABSTRACT The objective of this proposal is to identify linkages between T cell receptor (TCR) sequences and transcriptional profiles across the human T cell landscape. This work is enabled by our recent development of the CoNGA algorithm, a graph theoretic approach that integrates TCR and gene expression (GEX) datasets, and by technological advances that have made it possible to profile both features in parallel at high throughput. Submitted in response to Notice of Special Interest NOT-AI-21-011 ("Secondary Analysis of Existing Datasets for Advancing Immune-mediated and Infectious Disease Research"), our proposal brings together a team of computational biologists and immunologists with a track record of successful collaboration. Our goal is to apply CoNGA on diverse T cell datasets to define the landmark TCR features and their correlated phenotypes in human T cells. In the first Aim, we will identify, acquire, pre-process, and standardize all large, publicly available single-cell datasets that feature linked gene expression and paired TCR sequence information. We will then run the CoNGA pipeline on these individual datasets, correlate the results with available study metadata, and make these results available for download. In the second Aim, we will perform a meta-analysis of the relationship between T cell receptor sequence and T cell transcriptional profile across the entire dataset (1,000+ donors and 1,000,000+ individual T cells). Completion of the work proposed here will lay the groundwork for a comprehensive atlas of the human T cell landscape and provide a valuable dataset for further development of analytical tools and methods. T cell features and sub-populations identified by CoNGA will provide new insight into the individual datasets while also illuminating the global landscape of GEX/TCR covariation.

抽象的 该建议的目的是确定T细胞受体（TCR）序列和 人类T细胞景观的转录曲线。这项工作是通过我们最近发展的 CONCA算法是一种集成TCR和基因表达（GEX）数据集的理论方法， 并且通过技术进步，使得能够在高通量下并行介绍这两个功能。 提交的响应特殊利益通知而不是-AI-21-011（“现有数据集的二次分析 为了推进免疫介导的传染病研究”），我们的建议汇集了一个团队 具有成功协作的记录的计算生物学家和免疫学家。我们的目标是申请 Conga在不同的T细胞数据集上定义具有里程碑意义的TCR特征及其相关表型 人类T细胞。在第一个目标中，我们将确定，获取，预处理和标准化所有大型，公开的 可用的单细胞数据集具有链接的基因表达和配对的TCR序列信息。我们 然后，将在这些单独的数据集上运行CONGA管道，将结果与可用研究相关联 元数据，并使这些结果可供下载。在第二个目标中，我们将进行荟萃分析 T细胞受体序列与T细胞转录谱之间的关系之间的关系 （1,000多个供体和1,000,000多个单个T细胞）。在此提议的工作完成 为人类T细胞景观全面地图集的基础工作，并提供了一个有价值的数据集 开发分析工具和方法。 T细胞特征和Conga确定的子群将 提供有关单个数据集的新见解，同时还阐明了GEX/TCR的全球景观 协方差。