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

• 批准号: 8032514
• 负责人: Saumendra N Sarkar
• 金额: $ 28.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8032514
• 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

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）：生物体的先天免疫力是对入侵病原体的天生保护。先天性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因子。在这项提议中，我们打算靶向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，其将特异性地调节Toll样受体3、视黄酸诱导基因I和Toll样受体7信号通路。在这项研究的过程中，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剂，我们已经鉴定了参与TLR 3介导的IRF 3活化和细胞因子诱导的新的信号传导途径。在这项提案中，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，还可能为未来的药物开发提供构建模块，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因子的第一线传感器。我们建议靶向这些受体中的一些参与感知病毒感染，并确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异性试剂来治疗炎症和自身免疫性疾病，这些疾病是由这些受体的过度或不足引起的。