Novel Modifiers of Toll-like and RIG-like Receptor Signaling

描述(申请人提供)：生物体的先天免疫是对入侵病原体的先天保护。先天免疫受体感知入侵生物体的成分，并触发免疫和炎症反应，以对抗感染性病原体。在这项提议中，我们打算以三个人类先天免疫受体为目标，这些受体除其他外，参与检测病毒感染。我们将使用高通量筛选来寻找化学和小干扰RNA修饰物，它们将特异性地调节Toll样受体3、维甲酸诱导基因I和Toll样受体7信号通路。在本次调查过程中，我们希望找到有效的修饰剂，测试其特异性，并将其提供给研究界。 我们已经成功地开发并使用高通量筛选实验来靶向先天免疫受体之一-Toll样受体3。使用基于细胞的读出系统来筛选抑制物，我们发现了参与TLR3介导的IRF3激活和细胞因子诱导的新的信号通路。在这份提案中，我们将与匹兹堡大学药物发现研究所(DDI)合作，利用DDI的高通量筛查和药物开发专业知识来扩大我们的筛查工作。该项目不仅将产生研究先天免疫受体信号通路的新试剂，还可能为未来的药物开发提供基础，这些药物可用于治疗病毒感染引起的炎症性疾病。 相关性：先天免疫受体是识别入侵病原体的各种成分并触发免疫和炎症反应以对抗感染性病原体的第一线传感器。我们建议针对其中一些参与感知病毒感染的受体，并鉴定能够调节这些受体功能的新试剂。我们的长期目标是使用这些特定的试剂来治疗炎症性和自身免疫性疾病，这些疾病是由这些受体的过度或不足引起的。

DESCRIPTION (provided by applicant): Innate immunity of an organism is the in born protection against invading pathogens. Innate immune receptors sense components of invading organisms and trigger immune and inflammatory responses to combat infectious agents. In this proposal we intend to target three human innate immune receptors which among others are involved in detecting virus infection. We will use high throughput screening to identify chemical and small interfering RNA modifiers, which will specifically modulate Toll-like Receptor 3, Retinoic acid Inducible gene I and Toll-like receptor 7 signaling pathways. During the course of this investigation, we would like to find efficient modifiers, test their specificity, and make them available to the research community. We have successfully developed and used high throughput screening experiments to target one of the innate immune receptor - Toll-like Receptor 3. Using a cell-based readout system to screen for inhibitors we have identified novel signaling pathways involved in TLR3 mediated IRF3 activation and cytokine induction. In this proposal we will collaborate with University of Pittsburgh Drug Discovery Institute (DDI) to take advantage of the high throughput screening and drug development expertise of DDI to expand our screening efforts. This project will not only generate novel reagents for studying innate immune receptor signaling pathways, but may also provide building blocks for future drug development, which can be used to treat inflammatory diseases caused by virus infection. RELEVANCE: Innate immune receptors are the first line of sensors to recognize various components of invading pathogens and trigger immune and inflammatory responses to combat the infectious agent. We propose to target a few of these receptors which are involved in sensing virus infections, and identify novel reagents capable of modulating the functions of these receptors. Our long-term goal is to use these specific reagents to treat inflammatory and auto-immune diseases, which are caused by over or under-action of these receptors.