Automating the Discovery of Clinically-Relevant Intracellular Signaling Responses in Immune Cell-Types

项目摘要 单细胞免疫分析技术，如飞行时间流式细胞术（CyTOF），能够广泛和有效地检测免疫细胞。 不同免疫细胞类型的综合表征。此外，这些技术正在 越来越多地应用于临床环境，以获得免疫系统的整体视图。离体刺激是一种 应用于免疫细胞并通过CyTOF测定的常见扰动，其激发功能反应 这可能是临床预测。这样的实验产生大量的单细胞测量， 细胞，导致手动分析变得耗时，并偏向于研究免疫细胞类型 以及它们的功能反应已经被很好地描述了。现有的生物信息学方法 用于自动化手动分析的方法的局限性在于它们1）主要仅关注于将细胞划分为内聚的 细胞群，2）每次刺激需要独立运行，以及3）产生几种免疫学 编码对刺激的细胞类型特异性功能反应的特征， 免疫信号通路在本提案中，我们介绍了一种完全自动化的方法， 多样品、多刺激免疫谱数据的分析。特别是，我们将开发算法， 以可缩放的方式有效地识别对刺激的临床预测功能反应， 分析几种刺激条件下的大型临床队列。未覆盖的功能反应， 临床预测可用于开发诊断测试或设计疫苗，以引起特定的细胞 应答

Project Summary Single-cell immune profiling technologies, such as cytometry by time of flight (CyTOF) enable broad and comprehensive characterization of diverse immune cell-types. Moreover, such technologies are being increasingly applied in clinical settings to gain a holistic view of the immune system. Ex vivo stimulation is a common perturbation applied to immune cells and assayed through CyTOF, which elicits functional responses that may be clinically predictive. Such experiments generate single-cell measurements for a large number of cells, causing manual analysis to become time-consuming and biased towards studying immune cell-types and their functional responses that have already been well-characterized. Existing bioinformatics approaches for automating manual analysis are limited in that they 1) primarily focus only on partitioning cells into cohesive cell-populations, 2) need to be run independently per stimulation and 3) produce several immunological features encoding cell-type specific functional responses to stimulation that are not indicative of canonical immune signaling pathways. In this proposal, we introduce a fully automated approach for automating the analysis of multi-sample, multi-stimulation immune profiling data. In particular, we shall develop algorithms to efficiently identify clinically-predictive functional responses to stimulation in a scalable manner to enable analysis of large clinical cohorts under several stimulation conditions. Uncovered functional responses that are clinically predictive can be used to develop diagnostic tests or to design vaccines to elicit particular cellular responses.