Transcriptomics to define biomarkers of neonatal vaccine immunogenicity

项目摘要 在这里，我们建议利用网络生物学方法来识别与以下相关的转录签名 对免疫的保护性反应，并描述与之相关的途径、中枢和关键介质 有效的新生儿免疫接种。免疫系统是复杂的，由1500到5000个单独的基因组成 产品，以及表观遗传事件、miRNAs、翻译后修饰等。 认识到免疫系统与多个生理系统相结合，并受到 遗传、年龄、营养状况、性别、环境和潜在疾病或健康。学习个体 了解免疫过程的基因、蛋白质、途径和/或细胞类型为我们提供了一种 对健康和疾病中发生的细胞过程的错综复杂的不完整的图景。因此， 了解个体如何应对免疫挑战，例如接种疫苗，需要更全面的 系统级方法。我们开发了大量的技能集和工具，以实现 考虑新生儿/婴儿(和/或成人)血液中发生的所有基因表达事件，以及 以生物信息方式处理这些数据的方法，以实现面向网络的洞察，同时考虑所有因素 (称为元数据，包括人口统计数据和临床评估中的差异)，可能会起到 令人困惑的变量。特别是，我们将使用网络生物学来了解疫苗接种对 免疫状况以及最终哪些因素决定了个人接种疫苗的相对成功。我们的 转录学服务核心(SC1)将使用下一代测序开发转录学数据 RNA-Seq.下游分析将利用我们定制的数据库和分析工具。InnateDB 是我们广受欢迎的(600万次点击)所有基因的开源数据库和系统生物学分析平台， 蛋白质，包含实验验证的分子相互作用和先天免疫反应的途径 人类和其他物种。此外，我们还将应用我们最新的工具NetworkAnalyst Platform，它 采用统计、可视和基于网络的方法进行元分析和系统级解释 转录组和蛋白质组数据。NetworkAnalyst提供极快的网络布局、集线器分析和 可视化使得能够无偏地检查作为蛋白质-蛋白质相互作用的大型转录数据集 网络。通过对子网络、集线器和路径的信息进行挖掘，可以对数据和 对实验条件和刺激引起的差异的增值洞察力。关键的是，我们已经 消除了该项目的所有程序风险，包括样品采集、远程运输、RNA-Seq 和下游生物信息学分析，已经证明了我们有能力开发新的 我们的飞行员对疫苗诱导新生儿反应的潜在机制的见解/假设 学习。我们预计，我们的核心将为该项目的整体成功做出重大贡献。

Project Summary Here we propose to utilize Network Biology methods to identify transcriptomic signatures that correlate with protective responses to immunization and characterize the pathways, hubs, and key mediators associated with effective neonatal immunization. The immune system is complex and comprises 1,500 to 5,000 individual gene products, as well as epigenetic events, miRNAs, posttranslational modifications, etc. Furthermore it is well recognized that the immune system is integrated with multiple physiologic systems, and is influenced by genetics, age, nutritional status, gender, environment and underlying diseases or health. Studying individual genes, proteins, pathways and/or cell types to understand immune processes has provided us with an incomplete picture of the intricacies of the cellular processes that take place in both health and disease. Thus understanding how individuals respond to immune challenge, for example vaccination, requires a more holistic systems-level approach. We have developed a substantial collection of skill sets and tools to enable consideration of all gene expression events occurring in the blood of newborns/infants (and/or adults), and ways of bioinformatically handing these data to enable network-oriented insights while considering all factors (termed meta-data, and including demographics and differences in clinical assessments) that might act as confounding variables. In particular we will use Network Biology to understand the impact of vaccination on immune status and ultimately what factors determine the relative success of vaccination in individuals. Our Transcriptomics Service Core (SC1) will develop transcriptomic data using the next generation sequencing method of RNA-Seq. Downstream analyses will utilize our customized databases and analysis tools. InnateDB is our popular (>6 million hits) open-source database and systems biology analysis platform of all the genes, proteins, contains experimentally validated molecular interactions, and pathways in innate immune responses of humans and other species. In addition we will apply our newest tool, the NetworkAnalyst platform, which features statistical, visual and network-based approaches for meta-analysis and systems-level interpretation of transcriptomic, and proteomic data. NetworkAnalyst delivers extremely fast network layouts, hub analysis and visualization enabling unbiased examination of large transcriptomic datasets as protein-protein interaction networks. Mining of the information for subnetworks, hubs and pathways permits unique insights into data and value-added insights into differences due to experimental conditions and stimuli. Critically, we have already de-risked all procedures for this project including sample collection, transport from remote locations, RNA-Seq and downstream bioinformatic analysis and have already demonstrated our ability to develop new insights/hypotheses into the potential mechanisms driving vaccine-induced neonatal responses in our pilot studies. We anticipate that our Core will make a substantial contribution to the overall success of this project.