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

Toll 样和 RIG 样受体信号传导的新型修饰剂

基本信息

批准号：
8228166
负责人：
Saumendra N Sarkar
金额：
$ 28.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8228166
关键词：
Agonist Asthma Atherosclerosis Cell Line Cells Chemical Modifier Chemicals Clinical Trials Communities Custom Cytokine Activation Cytokine Gene Disease Double-Stranded RNA Effectiveness Enhancers Ensure Future Genes Genetic Goals Host Defense Human IRF3 gene Immune Immune System Diseases Immune response Immune system Immunologic Receptors Individual Infection Infectious Agent Inflammatory Inflammatory Response Institutes Invaded Investigation Libraries Mediating Methodology Microbiology Modification Molecular Bank Molecular Genetics Natural Immunity Organism Pathway interactions Principal Investigator Process Reagent Receptor Activation Receptor Signaling Regulator Genes Reporter Research Rheumatoid Arthritis Screening procedure Sendai virus Sepsis Series Shapes Signal Pathway Signal Transduction Small Interfering RNA Small Molecule Chemical Library Specificity System TLR3 gene TLR7 gene Testing Tissues Toll-like receptors Tretinoin Universities Up-Regulation Virus Diseases antimicrobial base combat defense response drug development drug discovery gene induction helicase high throughput screening human TLR3 protein human TLR7 protein inhibitor/antagonist insight microbial novel pathogen receptor receptor function research study sensor small molecule virology

项目摘要

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.

描述（由申请人提供）：生物体的先天免疫是针对入侵病原体的天生保护。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传染源。在这项提案中，我们打算针对三种人类先天免疫受体，其中包括参与检测病毒感染的受体。我们将使用高通量筛选来鉴定化学和小干扰 RNA 修饰剂，这些修饰剂将特异性调节 Toll 样受体 3、视黄酸诱导基因 I 和 Toll 样受体 7 信号通路。在这项调查过程中，我们希望找到有效的修饰剂，测试它们的特异性，并将它们提供给研究界。我们已经成功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剂，我们已经确定了参与 TLR3 介导的 IRF3 激活和细胞因子诱导的新信号传导途径。在本提案中，我们将与匹兹堡大学药物发现研究所 (DDI) 合作，利用 DDI 的高通量筛选和药物开发专业知识来扩大我们的筛选工作。该项目不仅将产生用于研究先天免疫受体信号通路的新型试剂，还可能为未来药物开发提供基础材料，用于治疗由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传染源的第一线传感器。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型试剂。我们的长期目标是使用这些特定试剂来治疗由这些受体过度或不足引起的炎症和自身免疫性疾病。