Systems Approach to Immunity and Inflammation

总结 先天免疫反应是一把双刃剑;它是宿主防御所必需的，但 不受控制，导致炎症性疾病。各种有效的机制已经发展起来， 对抗入侵的微生物。这些包括各种模式识别受体，包括Toll样 受体（TLR）、RIG-I样受体（RLR）、Nod样受体（NLR）和C型凝集素样受体 识别病原体上保守分子基序的CLRs。虽然在以下方面取得了重大进展： 通过识别这些受体检测到的配体以及它们激活的信号级联， 关于适当调整这些途径的输出的机制的关键问题仍然存在 无人回应 此外，对活病原体的免疫应答是由多种受体和 它们的同源信号通路。总体响应很复杂，无法通过分析进行预测 每一种途径都是孤立的;然而，使用系统生物学和正向遗传学的工具，它是容易处理的。 在过去的15年里，U19联盟的成员使用跨学科方法进行了合作 以确定免疫受体和途径调节的分子机制。他们的 遗传学方法还将这些途径与发病机理和体内免疫联系起来。这些研究 也产生了大量的工作，证明了先天免疫和免疫抑制之间的交叉调节。 受体。 U19由两个相互关联的项目组成，旨在探索对感染的先天免疫反应。在项目1中， Beutler实验室将与Aderem、Nolan和Ulevitch实验室密切合作， 一个高度自动化的遗传方法来分析先天免疫信号。在项目2中， Aderem实验室将确定TLR和I型干扰素途径交叉调节的机制 对方.该项目将得到三个科学核心的支持：信号核心，将承担 用于免疫细胞的高度多重分子表型分析的几种新技术。数据 管理和生物信息学核心将支持单个项目以及 通过对所有大规模数据集的综合计算分析，人际关系核心 将研究小鼠基因的相关性，在项目1和2中证明，介导先天免疫 在类似的人类途径中发挥作用。

Summary The innate immune response is a double-edged sword; it is absolutely required for host defense, but unregulated, causes inflammatory disease. Diverse and potent mechanisms have evolved to recognize and counter invading microorganisms. These include a variety of pattern recognition receptors, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs) and C-type lectin like receptors (CLRs) that recognize conserved molecular motifs on pathogens. While significant progress has been made in identifying the ligands detected by these receptors and the signaling cascades that they activate, a number of critical questions regarding the mechanisms that appropriately tailor the outputs of these pathways remain unanswered. Furthermore, the immune response to live pathogens is shaped by the interaction of multiple receptors and their cognate signaling pathways. The aggregate response is complex and cannot be predicted from analysis of each pathway in isolation; however, it is tractable using the tools of systems biology and forward genetics. Over the past 15 years members of this U19 consortium have collaborated using cross-disciplinary approaches to define the molecular mechanisms underlying the regulation of immune receptors and pathways. Their genetic approaches have also linked the pathways to pathogenesis and to immunity in vivo. These studies have also generated a significant body of work demonstrating cross-regulation between innate immune receptors. This U19 consists of two interrelated Projects that probe the innate immune response to infection. In Project 1, the Beutler laboratory will work in close collaboration with the Aderem, Nolan, and Ulevitch laboratories, taking a highly automated forward genetic approach to the analysis of innate immune signaling. In Project 2, the Aderem laboratory will determine mechanisms by which the TLR and type I interferon pathways cross-regulate each other. The Projects will be supported by three scientific Cores: The Signaling Core, will bring to bear several novel technologies for highly multiplexed molecular phenotyping of immune cells. The Data Management and Bioinformatics Core will support the individual Projects as well as the overall goals of the program through integrated computational analysis of all large-scale datasets. The Human Correlation Core will examine the relevance of mouse genes, demonstrated in Projects 1 and 2 to mediate innate immune functions, in the analogous human pathways.